5,6-disubstituted oxindole-derivatives and use thereof for treating vasopressin-dependent diseases

ABSTRACT

The present invention relates to novel 5,6-disubstituted oxindole derivatives and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such derivatives, and to the use of such derivatives for the manufacture of a medicament, and methods of treating disorders in a subject in need thereof, such as vasopressin-dependent disorders, using 5,6-disubstituted oxindole derivatives.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is the U.S. national stage entry of International PatentApplication No. PCT/EP2008/066935, filed on Dec. 5, 2008, which claimspriority to U.S. Provisional Patent Application No. 61/012,265, filedDec. 7, 2007, the contents of all of which are hereby incorporated byreference.

The present invention relates to novel substituted oxindole derivatives,pharmaceutical compositions comprising them, and their use for thetreatment of vasopressin-dependent disorders.

Vasopressin is an endogenous hormone which exerts various effects onorgans and tissues. It is suspected that the vasopressin system isinvolved in various pathological states such as, for example, heartfailure and high blood pressure. At present, three receptors (V1a, V1bor V3 and V2) via which vasopressin mediates its numerous effects areknown. Antagonists of these receptors are therefore being investigatedas possible new therapeutic approaches for the treatment of diseases (M.Thibonnier, Exp. Opin. Invest. Drugs 1998, 7(5), 729-740).

Novel substituted oxindoles having a phenylsulfonyl group in position 1are described herein. 1-Phenylsulfonyl-1,3-dihydro-2H-indol-2-ones havepreviously been described as ligands of vasopressin receptors. WO93/15051, WO 95/18105, WO 98/25901, WO 01/55130, WO 01/55134, WO01/164668 and WO 01/98295 also describe derivatives having arylsulfonylgroups in position 1 of the oxindole structure. These compounds differfrom the compounds of the invention essentially through the substituentsin position 3.

Thus, WO 93/15051 and WO 98/25901 describe1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones, in which the oxindolestructure is substituted in position 3 by two alkyl radicals which mayalso together form a cycloalkyl radical (spiro linkage), as ligands ofvasopressin receptors. As alternative, the spiro ring may compriseheteroatoms such as oxygen and nitrogen (optionally with substituents).

WO 95/18105 describes 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-oneshaving a nitrogen atom in position 3 as ligands of vasopressinreceptors. In addition, radicals selected from optionally substitutedalkyl, cycloalkyl, phenyl or benzyl radicals are bonded in position 3.

WO 03/008407 describes 1-phenylsulfonyloxindoles in whichpyridylpiperazines are linked via a urea, carbamate or 2-oxoethyl groupto the oxindole in position 3.

WO 2005/030755 relates to 1-phenylsulfonyloxindoles in whichpiperidylpiperazines or piperazinylpiperidines are linked via a urea,carbamate or 2-oxoethyl group to the oxindole in position 3. However,5,6-disubstituted oxindoles are not specifically described.

Besides the binding affinity for the vasopressin V1b receptor, furtherproperties may be advantageous for the treatment and/or prophylaxis ofvasopressin-dependent disorders, such as, for example:

1.) a selectivity for the vasopressin V1b receptor compared with thevasopressin V1a receptor, i.e. the quotient of the binding affinity forthe V1a receptor (Ki(V1a) (determined in the unit “nanomolar (nM)”) andthe binding affinity for the V1b receptor (Ki(V1b)) (determined in theunit “nanomolar (nM)”). A larger quotient Ki(V1a)/Ki(V1b) means agreater V1b selectivity;

2.) a selectivity for the vasopressin V1b receptor compared with thevasopressin V2 receptor, i.e. the quotient of the binding affinity forthe V2 receptor (Ki(V2) (determined in the unit “nanomolar (nM)”) andthe binding affinity for the V1b receptor (Ki(V1b)) (determined in theunit “nanomolar (nM)”). A larger quotient Ki(V2)/Ki(V1b) means a greaterV1b selectivity;

3.) a selectivity for the vasopressin V1b receptor compared with theoxytocin OT receptor, i.e. the quotient of the binding affinity for theOT receptor (Ki(OT) (determined in the unit “nanomolar (nM)”) and thebinding affinity for the V1b receptor (Ki(V1b)) (determined in the unit“nanomolar (nM)”). A larger quotient Ki(OT)/Ki(V1b) means a greater V1bselectivity.

4.) the metabolic stability, for example determined from the half-lives,measured in vitro, in liver microsomes from various species (e.g. rat orhuman);

5.) no or only low inhibition of cytochrome P450 (CYP) enzymes:cytochrome P450 (CYP) is the name for a superfamily of heme proteinshaving enzymatic activity (oxidase). They are also particularlyimportant for the degradation (metabolism) of foreign substances such asdrugs or xenobiotics in mammalian organisms. The principalrepresentatives of the types and subtypes of CYP in the human body are:CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g.grapefruit juice, cimetidine, erythromycin) are used at the same time asmedicinal substances which are degraded by this enzyme system and thuscompete for the same binding site on the enzyme, the degradation thereofmay be slowed down and thus effects and side effects of the administeredmedicinal substance may be undesirably enhanced;

6.) a suitable solubility in water (in mg/ml);

7.) suitable pharmacokinetics (time course of the concentration of thecompound of the invention in plasma or in tissue, for example brain).The pharmacokinetics can be described by the following parameters:half-life (in h), volume of distribution (in l·kg⁻¹), plasma clearance(in l·h⁻¹·kg⁻¹), AUC (area under the curve, area under theconcentration-time curve, in ng·h·l⁻¹), oral bioavailability (thedose-normalized ratio of AUC after oral administration and AUC afterintravenous administration), the so-called brain-plasma ratio (the ratioof AUC in brain tissue and AUC in plasma);

8.) no or only low blockade of the hERG channel: compounds which blockthe hERG channel may cause a prolongation of the QT interval and thuslead to serious disturbances of cardiac rhythm (for example so-called“torsade de pointes”). The potential of compounds to block the hERGchannel can be determined by means of the displacement assay withradiolabelled dofetilide which is described in the literature (G. J.Diaz et al., Journal of Pharmacological and Toxicological Methods, 50(2004), 187-199). A smaller IC50 in this dofetilide assay means agreater probability of potent hERG blockade. In addition, the blockadeof the hERG channel can be measured by electrophysiological experimentson cells which have been transfected with the hERG channel, by so-calledwhole-cell patch clamping (G. J. Diaz et al., Journal of Pharmacologicaland Toxicological Methods, 50 (2004), 187-199).

It was therefore an object of the present invention to provide compoundsfor the treatment or prophylaxis of various vasopressin-dependentdiseases. The compounds were intended to have a high activity andselectivity, especially a high affinity and selectivity vis-à-vis thevasopressin V1b receptor. In addition, the substance of the inventionwas intended to have one or more of the aforementioned advantages 1.) to8.).

The object is achieved by compounds of the formula I

in which

-   -   R¹ and R² are independently of one another hydrogen,        C₁-C₃-alkyl, C₁-C₃-fluoroalkyl, C₁-C₃-alkoxy,        C₁-C₃-fluoroalkoxy, halogen or CN;    -   R³ is hydrogen or C₁-C₄-alkyl;    -   R⁴ is ethoxy, fluorinated ethoxy or isopropoxy;    -   R⁵ is H or methyl;    -   R⁶ is Br, Cl, For CN;    -   R⁷ is Cl, F or CN;    -   R⁸ and R⁹ are independently of one another C₁-C₃-alkyl or        C₁-C₃-fluoroalkyl;    -   X¹ is O, NH or CH₂;    -   X² and X³ are N or CH, with the proviso that X² and X³ are not        simultaneously N;    -   X⁴ is N or CH;    -   a and b are independently of one another 0, 1 or 2; and    -   m, n, o and p are independently of one another 1, 2 or 3;    -   and their pharmaceutically acceptable salts and prodrugs        thereof.

Accordingly, the present invention relates to compounds of the formula I(also “compounds I” hereinafter) and the pharmaceutically acceptablesalts of the compounds I and the prodrugs of the compounds I.

The pharmaceutically acceptable salts of compounds of the formula I,which are also referred to as physiologically tolerated salts, areordinarily obtainable by reacting the free base of the compounds I ofthe invention (i.e. of the compounds I according to structural formulaI) with suitable acids. Examples of suitable acids are listed in“Fortschritte der Arzneimittelforschung”, 1966, Birkhäuser Verlag, vol.10, pp. 224-285. These include for example hydrochloric acid, citricacid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid,acetic acid, formic acid, maleic acid and fumaric acid.

The term “prodrugs” means compounds which are metabolized in vivo to thecompounds I of the invention. Typical examples of prodrugs are describedin C. G. Wermeth (editor): The Practice of Medicinal Chemistry, AcademicPress, San Diego, 1996, pages 671-715. These include for examplephosphates, carbamates, amino acids, esters, amides, peptides, ureas andthe like. Suitable prodrugs in the present case may be for examplecompounds I in which the outer nitrogen atom of the outernitrogen-containing ring forms an amide/peptide linkage by this nitrogenatom being substituted by a C₁-C₄-alkylcarbonyl group, e.g. by acetyl,propionyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl ortert-butylcarbonyl (pivaloyl), by benzoyl, or by an amino acid residuelinked via CO, e.g. glycine, alanine, serine, phenylalanine and the likelinked via CO, in the position of the radical R³. Further suitableprodrugs are alkylcarbonyloxyalkyl carbamates in which the outernitrogen atom of the outer nitrogen-containing ring has in the positionof the radical R³ a group of the formula —C(═O)—O—CHR^(a)—O—C(═O)—R^(b)in which R^(a) and R^(b) are independently of one another C₁-C₄-alkyl.Such carbamates are described for example in J. Alexander, R. Cargill,S. R. Michelson, H. Schwam, J. Medicinal Chem. 1988, 31(2), 318-322.These groups can then be eliminated under metabolic conditions andresult in compounds I in which R³ is H.

C₁-C₃-Alkyl is in the context of the present invention a linear orbranched alkyl radical having 1 to 3 carbon atoms, such as methyl,ethyl, n-propyl or isopropyl.

C₁-C₄-Alkyl is in the context of the present invention a linear orbranched alkyl radical having 1 to 4 carbon atoms, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

C₁-C₃-Fluoroalkyl is in the context of the present invention a linear orbranched alkyl radical having 1 to 3 carbon atoms as defined above, inwhich at least one hydrogen atom, e.g. 1, 2, 3, 4 or 5 hydrogen atoms,are replaced by fluorine atoms. Example thereof are fluoromethyl,difluoromethyl, trifluoromethyl, 1- and 2-fluoroethyl, 1,1-, 1,2- and2,2-difluoroethyl, 1,1,2-, 1,2,2 and 2,2,2-trifluoroethyl,1,1,2,2-tetrafluoroethyl, 1,2,2,2-tetrafluoroethyl, pentafluoroethyl,1-, 2- and 3-fluoroprop-1-yl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- and3,3-difluoroprop-1-yl, 1,1,2-, 1,2,2-, 1,1,3-, 2,2,3-, 1,2,3- and3,3,3-trifluoroprop-1-yl, 1- and 2-fluoroprop-2-yl, 1,1- and1,3-difluoroprop-2-yl, 1,1,1-trifluoroprop-2-yl and the like.

C₁-C₃-Alkoxy is in the context of the present invention a linear orbranched alkyl radical linked via an oxygen atom and having 1 to 3carbon atoms. Examples are methoxy, ethoxy, n-propoxy and isopropoxy.

C₁-C₃-Fluoroalkoxy is in the context of the present invention a linearor branched alkyl radical linked via an oxygen atom and having 1 to 3carbon atoms as defined above, in which at least one hydrogen atom, e.g.1, 2, 3, 4 or 5 hydrogen atoms, are replaced by fluorine atoms. Examplethereof are fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1- and2-fluoroethoxy, 1,1-, 1,2- and 2,2-difluoroethoxy, 1,1,2-, 1,2,2 and2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy,1,2,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-, 2- and3-fluoroprop-1-oxy, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- and3,3-difluoroprop-1-oxy, 1,1,2-, 1,2,2-, 1,1,3-, 2,2,3-, 1,2,3- and3,3,3-trifluoroprop-1-oxy, 1- and 2-fluoroprop-2-oxy, 1,1- and1,3-difluoroprop-2-oxy, 1,1,1-trifluoroprop-2-oxy and the like.

Fluorinated ethoxy is in the context of the present invention ethoxy inwhich 1, 2, 3, 4 or 5 of the hydrogen atoms are replaced by fluorineatoms. Examples are 1-fluoroethoxy, 2-fluoroethoxy, 1,1-difluoroethoxy,1,2-difluoroethoxy, 2,2-difluoroethoxy, 1,1,2-trifluoroethoxy,1,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy,1,2,2,2-tetrafluoroethoxy and 1,1,2,2,2-pentafluoroethoxy.

Halogen is in the context of the present invention fluorine, chlorine,bromine or iodine.

The compounds of the invention of the formula I, their pharmacologicallyacceptable salts and their prodrugs may also be present in the form ofsolvates or hydrates. Solvates mean in the context of the presentinvention crystalline forms of the compounds I or of theirpharmaceutically acceptable salts or prodrugs thereof which comprisesolvent molecules incorporated in the crystal lattice. The solventmolecules are preferably incorporated in stoichiometric ratios. Hydratesare a specific form of solvates; the solvent in this case is water.

The statements made hereinafter concerning suitable and preferredfeatures of the invention, especially concerning the variables R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, X¹, X², X³, X⁴, a, b, m, n, o and p in thecompound I, but also concerning the features of the process of theinvention and of the use according to the invention apply both taken ontheir own and preferably in any possible combination with one another.

The compounds I are preferably provided in the form of the free base(i.e. according to structural formula I) or in the form of their acidaddition salts.

In a preferred embodiment, R¹ and R² are independently of one anotherhydrogen, C₁-C₃-alkoxy or C₁-C₃-fluoroalkoxy. In this connection,C₁-C₃-alkoxy in the definition of the radicals R¹ and R² is preferablyethoxy or methoxy and is specifically methoxy. C₁-C₃-Fluoroalkoxy ispreferably C₁-C₂-fluoroalkoxy, i.e. is fluoromethoxy, difluoromethoxy,trifluoromethoxy, 1- and 2-fluoroethoxy, 1,1-, 1,2- and2,2-difluoroethoxy, 1,1,2-, 1,2,2 and 2,2,2-trifluoroethoxy,1,1,2,2-tetrafluoroethoxy, 1,2,2,2-tetrafluoroethoxy, pentafluoroethoxy,is preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy,2,2-difluoroethoxy and 2,2,2-trifluoroethoxy, and is specificallytrifluoromethoxy.

In a preferred embodiment, R¹ is hydrogen, methoxy, ethoxy,fluoromethoxy, difluoromethoxy or trifluoromethoxy, is particularlypreferably hydrogen, methoxy or trifluoromethoxy, is more preferablyhydrogen or methoxy and is specifically methoxy.

In a preferred embodiment, R² is hydrogen or methoxy and is specificallymethoxy.

In a particularly preferred embodiment, at least one of the radicals R¹and R² is methoxy. R¹ and R² are specifically methoxy.

In a preferred embodiment, R³ is hydrogen, methyl, ethyl, n-propyl orisopropyl, is particularly preferably hydrogen, methyl or ethyl, is inparticular methyl or ethyl and is specifically methyl.

In a preferred embodiment, R⁴ is ethoxy and R⁵ is H. In this case, X⁴ isN or CH and is preferably N.

In an alternatively preferred embodiment, R⁴ is ethoxy and R⁵ is methyl.In this case, X⁴ is preferably N.

In an alternatively preferred embodiment, R⁴ is isopropoxy and R⁵ is H.In this case, X⁴ is preferably N.

In an alternatively preferred embodiment, R⁴ is fluorinated ethoxy, ispreferably 2,2-difluoroethoxy or 2,2,2-trifluoroethoxy and isparticularly preferably 2,2-difluoroethoxy, and R⁵ is H. In this case,X⁴ is N or CH and is specifically CH.

X⁴ is particularly preferably N.

R⁴ is particularly preferably ethoxy and R⁵ is H. In this case, X⁴ is Nor CH and is preferably N.

In a preferred embodiment, R⁶ and R⁷ are not simultaneously CN.

At least one of the radicals R⁶ and R⁷ is preferably fluorine.Particularly preferably in this case R⁷ is fluorine and R⁶ is fluorine,chlorine, bromine or CN, is preferably fluorine, chlorine or CN and isparticularly preferably Cl or CN.

In a preferred embodiment, R⁸ and R⁹ are methyl or ethyl.

In a preferred embodiment, X¹ is NH.

In an alternatively preferred embodiment, X¹ is O.

In an alternatively preferred embodiment, X¹ is CH₂.

X¹ is particularly preferably NH or O and especially NH.

In a preferred embodiment, one of the variables X², X³ is N and theother is CH.

In a particularly preferred embodiment in this connection, X² is N andX³ is CH.

In an alternatively particularly preferred embodiment, X² is CH and X³is N.

In an alternatively preferred embodiment, both variables X², X³ are CH.

In a preferred embodiment, a and b are independently of one another 0 or1 and especially 0.

If a and/or b are not equal to 0, it is self-evident that the radicalsR⁸ and/or R⁹ are bonded to one of m, n, o or p CH₂ groups, where theyreplace in each case one hydrogen atom of this CH₂ group.

In a preferred embodiment, m, n, o and p are independently of oneanother 1 or 2.

Accordingly, m and n are preferably 1 or m and n are 2 or m is 1 and nis 2 or m is 2 and n is 1. It is particularly preferred for m and n tobe 2.

Accordingly, o and p are preferably 1 or o and p are 2 or o is 1 and pis 2 or o is 2 and p is 1. It is particularly preferred for o and p tobe 2.

In a particularly preferred embodiment, the present invention relates tocompounds of the formula I.A

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X¹, X², X³ and X⁴ have the generalmeanings indicated previously or in particular the preferred meaningsindicated previously.

The invention preferably relates to compounds of the formula I.A inwhich

-   -   R¹ is hydrogen, methoxy or trifluoromethoxy, preferably hydrogen        or methoxy;    -   R² is hydrogen or methoxy;    -   R³ is hydrogen, methyl, ethyl, n-propyl or isopropyl, preferably        hydrogen, methyl or ethyl, particularly preferably methyl or        ethyl    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl, F or CN, preferably Cl or CN;    -   R⁷ is F or Cl, preferably F;    -   X¹ is NH, O or CH₂;    -   X² is N or CH;    -   X³ is N or CH;    -   X⁴ is N,    -   where X² and X³ are not simultaneously N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention preferably relates alternatively to compounds of theformula I.A in which

-   -   R¹ is hydrogen, methoxy or trifluoromethoxy, preferably hydrogen        or methoxy;    -   R² is hydrogen or methoxy;    -   R³ is hydrogen, methyl, ethyl, n-propyl or isopropyl, preferably        hydrogen, methyl or ethyl, particularly preferably methyl or        ethyl;    -   R⁴ is 2,2-difluoroethoxy or ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl, F or CN, preferably Cl or CN;    -   R⁷ is F or Cl, preferably F;    -   X¹ is NH, O or CH₂;    -   X² is N or CH;    -   X³ is N or CH;    -   X⁴ is CH    -   where X² and X³ are not simultaneously N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention particularly preferably relates to compounds of theformula I.A in which

-   -   R¹ is hydrogen or methoxy;    -   R² is hydrogen or methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl, F or CN, preferably Cl or CN;    -   R⁷ is F or Cl, preferably F;    -   X¹ is NH, O or CH₂;    -   X² is N or CH;    -   X³ is N or CH;    -   X⁴ is N;    -   where X² and X³ are not simultaneously N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention particularly preferably relates alternatively to compoundsof the formula I.A in which

-   -   R¹ is hydrogen or methoxy;    -   R² is hydrogen or methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is 2,2-difluoroethoxy or ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl, F or CN, preferably Cl or CN;    -   R⁷ is F or Cl, preferably F;    -   X¹ is NH, O or CH₂;    -   X² is N or CH;    -   X³ is N or CH;    -   X⁴ is CH;    -   where X² and X³ are not simultaneously N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention more preferably relates to compounds of the formula I.A inwhich

-   -   R¹ is methoxy or H;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl, F or CN, preferably Cl or CN;    -   R⁷ is F;    -   X¹ is NH, O or CH₂;    -   X² is N or CH;    -   X³ is N or CH;    -   X⁴ is N;    -   where X² and X³ are not simultaneously N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention more preferably relates alternatively to compounds of theformula I.A in which

-   -   R¹ is methoxy or H;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl, F or CN, preferably Cl or CN;    -   R⁷ is F;    -   X¹ is NH, O or CH₂;    -   X² is N or CH;    -   X³ is N or CH;    -   X⁴ is CH;    -   where X² and X³ are not simultaneously N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention even more preferably relates to compounds of the formulaI.A in which

-   -   R¹ is methoxy;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl or CN;    -   R⁷ is F;    -   X¹ is NH;    -   X² is N;    -   X³ is CH;    -   X⁴ is N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention even more preferably relates alternatively to compounds ofthe formula I.A in which

-   -   R¹ is methoxy;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl or CN;    -   R⁷ is F;    -   X¹ is NH;    -   X² is CH;    -   X³ is N;    -   X⁴ is N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention even more preferably relates alternatively to compounds ofthe formula I.A in which

-   -   R¹ is methoxy;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl or CN;    -   R⁷ is F;    -   X¹ is CH₂;    -   X² is N;    -   X³ is CH;    -   X⁴ is N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention even more preferably relates alternatively to compounds ofthe formula I.A in which

-   -   R¹ is methoxy;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl or CN;    -   R⁷ is F;    -   X¹ is CH₂;    -   X² is CH;    -   X³ is N;    -   X⁴ is N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention even more preferably relates alternatively to compounds ofthe formula I.A in which

-   -   R¹ is methoxy or hydrogen;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl or CN;    -   R⁷ is F;    -   X¹ is O;    -   X² is N;    -   X³ is CH;    -   X⁴ is N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention even more preferably relates alternatively to compounds ofthe formula I.A in which

-   -   R¹ is methoxy or hydrogen;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl or CN;    -   R⁷ is F;    -   X¹ is O;    -   X² is CH;    -   X³ is N;    -   X⁴ is N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention even more preferably relates alternatively to compounds ofthe formula I.A in which

-   -   R¹ is methoxy or hydrogen;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl or CN;    -   R⁷ is F;    -   X¹ is NH;    -   X² is N;    -   X³ is CH;    -   X⁴ is CH;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention even more preferably relates alternatively to compounds ofthe formula I.A in which

-   -   R¹ is methoxy or hydrogen;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl or CN;    -   R⁷ is F;    -   X¹ is NH;    -   X² is CH;    -   X³ is N;    -   X⁴ is CH;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention particularly relates to compounds of the formula I.A inwhich

-   -   R¹ is methoxy;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl;    -   R⁷ is F;    -   X¹ is NH;    -   X² is N;    -   X³ is CH;    -   X⁴ is N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention also particularly relates to compounds of the formula I.Ain which

-   -   R¹ is methoxy;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl;    -   R⁷ is F;    -   X¹ is NH;    -   X² is CH;    -   X³ is N;    -   X⁴ is N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention also particularly relates to compounds of the formula I.Ain which

-   -   R¹ is methoxy;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl;    -   R⁷ is F;    -   X¹ is CH₂;    -   X² is N;    -   X³ is CH;    -   X⁴ is N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention also particularly relates to compounds of the formula I.Ain which

-   -   R¹ is methoxy;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is Cl;    -   R⁷ is F;    -   X¹ is CH₂;    -   X² is CH;    -   X³ is N;    -   X⁴ is N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention also particularly relates to compounds of the formula I.Ain which

-   -   R¹ is methoxy;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is CN;    -   R⁷ is F;    -   X¹ is NH;    -   X² is N;    -   X³ is CH;    -   X⁴ is N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention also particularly relates to compounds of the formula I.Ain which

-   -   R¹ is methoxy;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is CN;    -   R⁷ is F;    -   X¹ is NH;    -   X² is CH;    -   X³ is N;    -   X⁴ is N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention also particularly relates to compounds of the formula I.Ain which

-   -   R¹ is methoxy or hydrogen;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is CN;    -   R⁷ is F;    -   X¹ is O;    -   X² is N;    -   X³ is CH;    -   X⁴ is N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

The invention also particularly relates to compounds of the formula I.Ain which

-   -   R¹ is methoxy or hydrogen;    -   R² is methoxy;    -   R³ is methyl or ethyl;    -   R⁴ is ethoxy;    -   R⁵ is hydrogen;    -   R⁶ is CN;    -   R⁷ is F;    -   X¹ is O;    -   X² is CH;    -   X³ is N;    -   X⁴ is N;    -   and the pharmaceutically acceptable salts and prodrugs thereof.

Examples of preferred embodiment of the present invention are compoundsof the formula I.1 to I.60 and the pharmaceutically acceptable salts andprodrugs thereof, in which the radicals X², X³, R¹, R² and R³ assume ineach case the meanings mentioned in each line in the following table 1.

TABLE 1 Example No. X² X³ R¹ R² R³ A-1. N CH Methoxy Methoxy Methyl A-2.N CH Methoxy H Methyl A-3. N CH Ethoxy H Methyl A-4. N CH H H MethylA-5. N CH H Methoxy Methyl A-6. N CH Ethoxy Methoxy Methyl A-7. N CHMethoxy Methoxy Ethyl A-8. N CH Methoxy H Ethyl A-9. N CH Ethoxy H EthylA-10. N CH H H Ethyl A-11. N CH H Methoxy Ethyl A-12. N CH EthoxyMethoxy Ethyl A-13. N CH Methoxy Methoxy n-Propyl A-14. N CH Methoxy Hn-Propyl A-15. N CH Ethoxy H n-Propyl A-16. N CH H H n-Propyl A-17. N CHH Methoxy n-Propyl A-18. N CH Ethoxy Methoxy n-Propyl A-19. N CH MethoxyMethoxy Isopropyl A-20. N CH Methoxy H Isopropyl A-21. N CH Ethoxy HIsopropyl A-22. N CH H H Isopropyl A-23. N CH H Methoxy Isopropyl A-24.N CH Ethoxy Methoxy Isopropyl A-25. N CH Methoxy Methoxy H A-26. N CHMethoxy H H A-27. N CH Ethoxy H H A-28. N CH H H H A-29. N CH H MethoxyH A-30. N CH Ethoxy Methoxy H A-31. CH N Methoxy Methoxy Methyl A-32. CHN Methoxy H Methyl A-33. CH N Ethoxy H Methyl A-34. CH N H H MethylA-35. CH N H Methoxy Methyl A-36. CH N Ethoxy Methoxy Methyl A-37. CH NMethoxy Methoxy Ethyl A-38. CH N Methoxy H Ethyl A-39. CH N Ethoxy HEthyl A-40. CH N H H Ethyl A-41. CH N H Methoxy Ethyl A-42. CH N EthoxyMethoxy Ethyl A-43. CH N Methoxy Methoxy n-Propyl A-44. CH N Methoxy Hn-Propyl A-45. CH N Ethoxy H n-Propyl A-46. CH N H H n-Propyl A-47. CH NH Methoxy n-Propyl A-48. CH N Ethoxy Methoxy n-Propyl A-49. CH N MethoxyMethoxy Isopropyl A-50. CH N Methoxy H Isopropyl A-51. CH N Ethoxy HIsopropyl A-52. CH N H H Isopropyl A-53. CH N H Methoxy Isopropyl A-54.CH N Ethoxy Methoxy Isopropyl A-55. CH N Methoxy Methoxy H A-56. CH NMethoxy H H A-57. CH N Ethoxy H H A-58. CH N H H H A-59. CH N H MethoxyH A-60. CH N Ethoxy Methoxy H A-61. CH CH Methoxy Methoxy Methyl A-62.CH CH Methoxy H Methyl A-63. CH CH Ethoxy H Methyl A-64. CH CH H HMethyl A-65. CH CH H Methoxy Methyl A-66. CH CH Ethoxy Methoxy MethylA-67. CH CH Methoxy Methoxy Ethyl A-68. CH CH Methoxy H Ethyl A-69. CHCH Ethoxy H Ethyl A-70. CH CH H H Ethyl A-71. CH CH H Methoxy EthylA-72. CH CH Ethoxy Methoxy Ethyl A-73. CH CH Methoxy Methoxy n-PropylA-74. CH CH Methoxy H n-Propyl A-75. CH CH Ethoxy H n-Propyl A-76. CH CHH H n-Propyl A-77. CH CH H Methoxy n-Propyl A-78. CH CH Ethoxy Methoxyn-Propyl A-79. CH CH Methoxy Methoxy Isopropyl A-80. CH CH Methoxy HIsopropyl A-81. CH CH Ethoxy H Isopropyl A-82. CH CH H H Isopropyl A-83.CH CH H Methoxy Isopropyl A-84. CH CH Ethoxy Methoxy Isopropyl A-85. CHCH Methoxy Methoxy H A-86. CH CH Methoxy H H A-87. CH CH Ethoxy H HA-88. CH CH H H H A-89. CH CH H Methoxy H A-90. CH CH Ethoxy Methoxy H

The compounds preferred among the compounds I.1 to I.60 mentioned aboveare those of the formulae I.1, I.2, I.5, I.6, I.7, I.10, I.11, I.12,I.15, I.16, I.17, I.20, I.21, I.22, I.25, I.26, I.27, I.30, I.31, I.32,I.35, I.36, I.37, I.40, I.41, I.42, I.45, I.46, I.47, I.50, I.51, I.52,I.55, I.56, I.57 and I.60, in which the radicals X², X³, R¹, R² and R³assume in each case the meanings mentioned in each line in table 1.Compounds among these which are in turn preferred are those of theformulae I.1, I.2, I.6, I.7, I.11, I.12, I.16, I.17, I.21, I.22, I.26,I.27, I.31, I.32, I.36, I.37, I.41, I.42, I.46, I.47, I.51, I.52, I.56and I.57, in which the radicals X², X³, R¹, R² and R³ assume in eachcase the meanings mentioned in each line in table 1. Compounds morepreferred among these are those of the formulae I.1, I.2, I.6, I.7,I.11, I.12, I.16, I.17, I.21, I.22, I.26 and I.27, in which the radicalsX², X³, R¹, R² and R³ assume in each case the meanings mentioned in eachline in table 1. Compounds particularly preferred among these are thoseof the formulae I.1, I.2, I.6, I.7, I.11 and I.12, in which the radicalsX², X³, R¹, R² and R³ assume in each case the meanings mentioned in eachline in table 1. Very particularly preferred compounds among these arethose of the formulae I.1 and I.2, in which the radicals X², X³, R¹, R²and R³ assume in each case the meanings mentioned in each line in table1.

The compounds I of the invention have a center of chirality in position3 of the 2-oxindole ring. The compounds of the invention may thereforebe in the form of a 1:1 mixture of enantiomers (racemate) or of anonracemic mixture of enantiomers in which one of the two enantiomers,either the enantiomer which rotates the plane of vibration of linearlypolarized light to the left (i.e. minus rotation) (hereinafter (−)enantiomer) or the enantiomer which rotates the plane of vibration oflinearly polarized light to the right (i.e. plus rotation) (hereinafter(+) enantiomer), is enriched, or of substantially enantiopure compounds,that is to say of substantially enantiopure (−) enantiomer or (+)enantiomer. Since the compounds of the invention have a single center ofasymmetry and no axis/plane of chirality, a nonracemic mixture can alsobe defined as a mixture of enantiomers in which either the R or the Senantiomer predominates. Substantially enantiopure compounds canaccordingly also be defined as substantially enantiopure R enantiomer orsubstantially enantiopure S enantiomer.

“Substantially enantiopure compounds” means in the context of thepresent invention those compounds having an enantiomeric excess (ee; %ee=(R−S)/(R+S)×100 or (S−R)/(S+R)×100) of at least 80% ee, preferably atleast 85% ee, more preferably at least 90% ee, even more preferably atleast 95% ee and in particular at least 98% ee.

In one embodiment of the invention, the compounds of the invention arein the form of substantially enantiopure compounds. Particularlypreferred compounds have an enantiomeric excess of at least 85% ee, morepreferably of at least 90% ee, even more preferably of at least 95% eeand in particular of at least 98% ee.

The invention thus relates both to the pure enantiomers and to mixturesthereof, e.g. mixtures in which one enantiomer is present in enrichedform, but also to the racemates. The invention also relates to thepharmaceutically acceptable salts and the prodrugs of the pureenantiomers of compounds I, and the racemic and nonracemic mixtures ofenantiomers in the form of the pharmaceutically acceptable salts andprodrugs of compounds I.

The statements made in the context of the present invention concerningthe direction of rotation of polarized light relate preferably to thesigns [(+) or (−)] as determined in chloroform as solvent or inchloroform-containing solvent mixtures, in particular in chloroform.

Examples of synthetic routes for preparing the oxindole derivatives ofthe invention are described below.

The compounds of the invention can be prepared by using methodsdescribed in WO 2005/030755 and WO 2006/005609 for synthesizinganalogous compounds, and the preparation is outlined by way of examplein synthesis schemes 1 to 3. The variables in these synthetic schemeshave the same meanings as in formula I.

The 3-hydroxy-1,3-dihydroindol-2-ones IV can be obtained by addition ofmetallated benzenes or heterocycles III onto the 3-keto group of theisatins II. The metallated benzenes or heterocycles, such as, forexample, the corresponding Grignard (Mg) or organyllithium compound, canbe obtained in any conventional way from halogen or hydrocarboncompounds. Examples of methods are present in Houben-Weyl, Methoden derOrganischen Chemie, vol. 13, 1-2, chapter on Mg and Li compounds. Theisatins II are either commercially available or were prepared in analogyto methods described in the literature (Advances in HeterocyclicChemistry, A. R. Katritzky and A. J. Boulton, Academic Press, New York,1975, 18, 2-58; J. Brazil. Chem. Soc. 12, 273-324, 2001).

The 3-hydroxyoxindoles IV which comprise an iodine in the 6-memberedaromatic ring, for example in position 5 or 6, i.e. in the position ofthe radicals R⁶ or R⁷, can be converted with KCN or Zn(CN)₂ with Pd(0)catalysis in solvents such as dimethylformamide or tetrahydrofuran,where appropriate also with addition of bases such as K₂CO₃ or othercarbonates or amines, at elevated temperature into the analogouscyan-containing 3-hydroxyoxindole IV. Pd(0) salts which can be taken arefor example transition metal complexes which are prepared in situ fromPdCl₂ or PdOAc₂ by addition of phosphines such astris(orthotolyl)phosphine. It is likewise possible to employ commercialpalladium complexes such as, for example, the catalysttetrakis(triphenylphosphine)palladium(0) and/or additions of phosphineligands.

The 3-hydroxyoxindoles IV can be converted into the compounds V whichhave a leaving group LG′ in position 3, where the leaving group LG′ is aconventional leaving group such as, for example, chlorine or bromide.The intermediate V with for example LG′=chlorine can be prepared bytreating the alcohol IV with thionyl chloride in the presence of a basesuch as, for example, pyridine, in a suitable solvent such as, forexample, dichloromethane.

The compounds V can subsequently be reacted with amines, such as, forexample, ammonia, in a substitution reaction to give the amines VI. Thecompounds VI can subsequently be converted by treatment with sulfonylchlorides VII after deprotonation with a strong base such as, forexample, potassium tert-butoxide or sodium hydride in DMF into thesulfonylated product VIII. The sulfonyl chlorides VII employed caneither be purchased or be prepared by known processes (for example J.Med. Chem. 40, 1149 (1997)).

The compounds of the invention of the general formula I which have aurea group in position 3 can be prepared as described in WO 2005/030755and WO 2006/005609, and shown in synthesis scheme 1, in a two-stageprocess: firstly, the compounds VIII are reacted with phenylchloroformate in the presence of a base such as, for example, pyridineto give the corresponding phenyl carbamate IX.

Subsequent reaction with amines X, where appropriate at elevatedtemperature and with the addition of auxiliary bases such as, forexample, triethylamine or diisopropylethyl-amine, leads to the compoundsof the invention of the general formula (I) with a urea bridge (X¹═NH).The amines X can be either purchased or prepared by methods known fromthe literature. Compounds I of the invention with R³═H can be preparedby using appropriate Boc-protected amines (R³=Boc). The Boc protectivegroup can subsequently be removed, for example by treatment withtrifluoroacetic acid in dichloromethane.

The compounds of the invention of the general formula I having acarbamate group in position 3 (X¹═O) can be prepared as described in WO2006/005609 and shown in synthesis scheme 2: firstly, the 3-hydroxycompound IV is reacted with phenyl chloroformate to give the phenylcarbonate derivatives XIa and/or XIb. The carbamate derivatives XII areobtained with an excess of amine X and can subsequently be convertedunder the usual conditions (deprotonation with a strong base such as,for example, sodium hydride or potassium tert-butoxide in a suitablesolvent such as, for example, DMF, followed by treatment with sulfonylchlorides VII) into the compounds I of the invention with a carbamatebridge.

The compounds of the invention of the general formula I which have a2-oxoethyl group in position 3 (X¹═CH₂) can be prepared as shown insynthesis scheme 3. Introduction of the acetic acid group can take placeas described in WO 2006/005609 in a 4-stage sequence (1. replacement ofthe leaving group LG′ in V by the sodium salt of dimethyl malonate, 2.hydrolysis of the first ester group, 3. thermal decarboxylation, 4.hydrolysis of the second ester group). The amine side chain X can becoupled to the carboxylic acid XV using standard coupling reagents knownin peptide chemistry, such as, for example, EDC(N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride) and HOBT(1-hydroxybenzo-triazole) in a solvent such as, for example,N,N-dimethylformamide, or BOP(1-benzo-triazolyloxytris(dimethylamino)phosphonium hexafluorophosphate)in the presence of a base such as triethylamine or diisopropyethylamine.The sulfonylation can take place by deprotonation of the couplingproduct XVI with a strong base such as, for example, sodium hydride orpotassium tert-butoxide, and subsequent treatment with sulfonylchlorides VII in a solvent such as, for example, DMF, and leads to thecompounds I of the invention with an amide bridge.

A further aspect of the present invention relates to a pharmaceuticalcomposition comprising at least one compound of the general formula Iand/or a pharmaceutically acceptable salt or a prodrug thereof asdetailed above, and a pharmaceutically acceptable carrier. Suitablecarriers depend inter alia on the dosage form of the composition and areknown in principle to the skilled worker. Some suitable carriers aredescribed hereinafter.

A further aspect of the present invention relates to the use ofcompounds of the formula I and/or of pharmaceutically acceptable saltsor prodrugs thereof for the manufacture of a medicament for thetreatment and/or prophylaxis of vasopressin-dependent diseases.

Vasopressin-dependent diseases are those in which the progress of thedisease is at least partly dependent on vasopressin, i.e. diseases whichshow an elevated vasopressin level which may contribute directly orindirectly to the pathological condition. In other words,vasopressin-dependent diseases are those which can be influenced bymodulating the vasopressin receptor, for example by administration of avasopressin receptor ligand (agonist, antagonist, partialantagonist/agonist, inverse agonist etc.).

In a preferred embodiment, the present invention relates to the use ofcompounds of the invention of the formula I or of pharmaceuticallyacceptable salts or prodrugs for the manufacture of a medicament for thetreatment and/or prophylaxis of diseases selected from diabetes, insulinresistance, nocturnal enuresis, incontinence and diseases in whichimpairments of blood clotting occur, and/or for delaying micturition.The term “diabetes” means all types of diabetes, especially diabetesmellitus (including type I and especially type II), diabetes renalis andin particular diabetes insipidus. The types of diabetes are preferablydiabetes mellitus of type II (with insulin resistance) or diabetesinsipidus.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofdiseases selected from hypertension, pulmonary hypertension, heartfailure, myocardial infarction, coronary spasm, unstable angina, PTCA(percutaneous transluminal coronary angioplasty), ischemias of theheart, impairments of the renal system, edemas, renal vasospasm,necrosis of the renal cortex, hyponatremia, hypokalemia,Schwartz-Bartter syndrome, impairments of the gastrointestinal tract,gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcers,emesis, emesis occurring during chemotherapy, and travel sickness.

The compounds of the invention of the formula I or theirpharmaceutically acceptable salts or prodrugs or the pharmaceuticalcomposition of the invention can also be used for the treatment ofvarious vasopressin-dependent complaints which have central nervouscauses or alterations in the HPA axis (hypothalamic pituitary adrenalaxis), for example for affective disorders such as depressive disordersand bipolar disorders. These include for example dysthymic disorders,phobias, post-traumatic stress disorders, general anxiety disorders,panic disorders, seasonal depression and sleep disorders.

The compounds of the invention of the formula I and theirpharmaceutically acceptable salts or prodrugs or the pharmaceuticalcomposition of the invention can likewise be employed for the treatmentof anxiety disorders and stress-dependent anxiety disorders, such as,for example, generalized anxiety disorders, phobias, post-traumaticanxiety disorders, panic anxiety disorders, obsessive-compulsive anxietydisorders, acute stress-dependent anxiety disorders and social phobia.

The compounds of the invention can furthermore also be employed for thetreatment of memory impairments, Alzheimer's disease, psychoses,psychotic disorders, sleep disorders and/or Cushing's syndrome, and allstress-dependent diseases.

Accordingly, a further preferred embodiment of the present inventionrelates to the use of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of affective disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of anxiety disordersand/or stress-dependent anxiety disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of memory impairmentsand/or Alzheimer's disease.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of psychoses and/orpsychotic disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of Cushing's syndrome orother stress-dependent diseases.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of sleep disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of depressive disorders. Aparticular form of depressive disorders are so-called childhood onsetmood disorders, i.e. depressive moods having their onset in childhood.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of vasomotor symptomsand/or thermoregulatory dysfunctions such as, for example, the hot flushsymptom.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment and/or prophylaxis of drugor pharmaceutical dependencies and/or dependencies mediated by otherfactors, for the treatment and/or prophylaxis of stress caused bywithdrawal of one or more factors mediating the dependence and/or forthe treatment and/or prophylaxis of stress-induced relapses into drug orpharmaceutical dependencies and/or dependencies mediated by otherfactors.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofschizophrenia and/or psychosis.

A further aspect of the invention relates to a method for the treatmentand/or prophylaxis of vasopressin-dependent diseases, in which aneffective amount of at least one compound of the invention of theformula I or of at least one pharmaceutically acceptable salt or oneprodrug thereof or of a pharmaceutical composition of the invention isadministered to a patient.

Concerning the definition of vasopressin-dependent diseases, referenceis made to the above statements.

In a preferred embodiment of the invention, the method of the inventionserves for the treatment and/or prophylaxis of disorders selected fromdiabetes, insulin resistance, nocturnal enuresis, incontinence anddiseases in which impairments of blood clotting occur, and/or fordelaying micturition. Concerning the definition of diabetes, referenceis made to the above statements.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of disorders selected fromhypertension, pulmonary hypertension, heart failure, myocardialinfarction, coronary spasm, unstable angina, PTCA (percutaneoustransluminal coronary angioplasty), ischemias of the heart, impairmentsof the renal system, edemas, renal vasospasm, necrosis of the renalcortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome,impairments of the gastrointestinal tract, gastritic vasospasm,hepatocirrhosis, gastric and intestinal ulcers, emesis, emesis occurringduring chemotherapy, and travel sickness.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of affective disorders.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of anxiety disorders and/orstress-dependent anxiety disorders.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of memory impairments and/orAlzheimer's disease.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of psychoses and/or psychoticdisorders.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of Cushing's syndrome.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of sleep disorders in a patient.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of depressive disorders. In thecase of depressive disorders, specific mention is also to be made ofchildhood onset mood disorders, i.e. depressive moods having their onsetin childhood.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of vasomotor symptoms and/orthermoregulatory dysfunctions, such as, for example, the hot flushsymptom.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of drug or pharmaceuticaldependencies and/or dependencies mediated by other factors, for thetreatment and/or prophylaxis of stress caused by withdrawal of one ormore factors mediating the dependence, and/or for the treatment and/orprophylaxis of stress-induced relapses into drug or pharmaceuticaldependencies and/or dependencies mediated by other factors.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of schizophrenia and/or psychosis.

The patient to be treated prophylactically or therapeutically with themethod of the invention is preferably a mammal, for example a human or anonhuman mammal or a nonhuman transgenic mammal. Specifically it is ahuman.

The compounds of the general formula I, their pharmaceuticallyacceptable salts and prodrugs as detailed above can be prepared by askilled worker with knowledge of the technical teaching of the inventionin implementing and/or in analogous implementation of process stepsknown per se.

The compounds I or their prodrugs and/or their pharmaceuticallyacceptable salts are distinguished by having a selectivity for thevasopressin V1b receptor subtype vis-à-vis at least one of the closelyrelated vasopressin/oxytocin receptor subtypes (for example vasopressinV1a, vasopressin V2 and/or oxytocin).

Alternatively, or preferably in addition, the compounds I or theirprodrugs and/or their pharmaceutically acceptable salts aredistinguished by having an improved metabolic stability.

The metabolic stability of a compound can be measured for example byincubating a solution of this compound with liver microsomes fromparticular species (for example rat, dog or human) and determining thehalf-life of the compound under these conditions (R S Obach, Curr OpinDrug Discov Devel. 2001, 4, 36-44). It is possible in this connection toconclude from an observed longer half-life that the metabolic stabilityof the compound is improved. The stability in the presence of humanliver microsomes is of particular interest because it makes it possibleto predict the metabolic degradation of the compound in the human liver.Compounds with increased metabolic stability (measured in the livermicrosome test) are therefore probably also degraded more slowly in theliver. The slower metabolic degradation in the liver may lead to higherand/or longer-lasting concentrations (active levels) of the compound inthe body, so that the elimination half-life of the compounds of theinvention is increased. Increased and/or longer-lasting active levelsmay lead to a better activity of the compound in the treatment orprophylaxis of various vasopressin-dependent diseases. In addition, animproved metabolic stability may lead to an increased bioavailabilityafter oral administration, because the compound is subject, afterabsorption in the intestine, to less metabolic degradation in the liver(so-called first pass effect). An increased oral bioavailability may,owing to an increased concentration (active level) of the compound, leadto a better activity of the compound after oral administration.

Alternatively, or preferably in addition, the compounds I or theirprodrugs and/or their pharmaceutically acceptable salts aredistinguished by having an improved pharmacological activity, comparedwith the oxindole compounds known from the prior art, in patients orrelevant animal models which enable prognostic statements for use in thetreatment.

The compounds of the invention are effective after administration byvarious routes. Possible examples are intravenous, intramuscular,subcutaneous, topical, intratracheal, intranasal, transdermal, vaginal,rectal, sublingual, buccal or oral administration, and administration isfrequently intravenous, intramuscular or, in particular, oral.

The present invention also relates to pharmaceutical compositions whichcomprise an effective dose of a compound I of the invention, of apharmaceutically acceptable salt or of a prodrug thereof and suitablepharmaceutical carriers (drug carriers).

These drug carriers are chosen according to the pharmaceutical form andthe desired mode of administration and are known in principle to theskilled worker.

The compounds of the invention of the formula I or optionally suitablesalts of these compounds can be used to produce pharmaceuticalcompositions for oral, sublingual, buccal, subcutaneous, intramuscular,intravenous, topical, intratracheal, intranasal, transdermal, vaginal orrectal administration, and be administered to animals or humans inuniform administration forms, mixed with conventional pharmaceuticalcarriers, for the prophylaxis or treatment of the above disorders ordiseases.

The suitable administration forms (dose units) include forms for oraladministration such as tablets, gelatin capsules, powders, granules andsolutions or suspensions for oral intake, forms for sublingual, buccal,intratracheal or intranasal administration, aerosols, implants, forms ofsubcutaneous, intramuscular or intravenous administration and forms ofrectal administration.

The compounds of the invention can be used in creams, ointments orlotions for topical administration.

In order to achieve the desired prophylactic or therapeutic effect, thedose of the active ingredient can vary between 0.01 and 50 mg per kg ofbody weight and per day.

Each unit dose may comprise from 0.05 to 5000 mg, preferably 1 to 1000mg, of the active ingredient in combination with a pharmaceuticalcarrier. This unit dose can be administered once to 5 times a day, sothat a daily dose of from 0.5 to 25 000 mg, preferably 1 to 5000 mg, isadministered.

If a solid composition is prepared in the form of tablets, the activeingredient is mixed with a solid pharmaceutical carrier such as gelatin,starch, lactose, magnesium stearate, talc, silicon dioxide or the like.

The tablets can be coated with sucrose, a cellulose derivative oranother suitable substance or be treated otherwise in order to display asustained or delayed activity and to release a predetermined amount ofthe active ingredient continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with an extender and including the resulting mixturein soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration inthe form of drops may contain active ingredients together with asweetener, which is preferably calorie-free, methylparaben orpropylparaben as antiseptics, a flavoring and a suitable coloringsubstance.

Water-dispersible powders or granules may comprise the activeingredients mixed with dispersants, wetting agents or suspending agents,such as polyvinylpyrrolidones, and sweeteners or masking flavors.

Rectal or vaginal administration is achieved by using suppositorieswhich are prepared with binders which melt at rectal temperature, forexample cocoa butter or polyethylene glycols. Parenteral administrationis effected by using aqueous suspensions, isotonic saline solutions orsterile and injectable solutions which comprise pharmacologicallyacceptable dispersants and/or wetting agents, for example propyleneglycol or polyethylene glycol.

The active ingredient may also be formulated as microcapsules orcentrosomes, if suitable with one or more carriers or additives.

The compositions of the invention may, in addition to the compounds ofthe invention, comprise other active ingredients which may be beneficialfor the treatment of the disorders or diseases indicated above.

The present invention thus further relates to pharmaceuticalcompositions in which a plurality of active ingredients are presenttogether, where at least one of these is a compound I of the invention,salt or a prodrug thereof.

The invention is explained in more detail below by means of examples,but the examples are not to be understood to be restrictive.

The compounds of the invention can be prepared by various syntheticroutes. The methods mentioned, as described accordingly in synthesisschemes 1, 2 and 3, are explained in greater detail merely by way ofexample using the given examples without being exclusively restricted tosynthesis routes 1, 2 or 3 or analogous methods.

EXPERIMENTAL SECTION

Abbreviations Used:

THF: Tetrahydrofuran

DMSO: Dimethyl sulfoxide

TFA: Trifluoroacetic acid

BOP: 1-Benzotriazolyloxytris(dimethylamino)phosphoniumhexafluorophosphate

p: pseudo (for example pt pseudo triplet)

b: broad (for example bs broad singlet)

s: singlet

d: doublet

t: triplet

m: multiplet

dd: doublet of doublets

dt: doublet of triplets

tt: triplet of triplets

I. Preparation of the Intermediate Compounds

5,6-Difluoroisatin is commercially available for example from thesuppliers ASYMCHEM, BUTT PARK, TIMECHEM and UKRORGSYN-BB.

5-Bromo-6-fluoroisatin is commercially available for example from thesuppliers BUTT PARK and UKRORGSYN-BB.

5-Chloro-6-fluoroisatin is commercially available for example from thesupplier UKRORGSYN-BB.

5-Fluoro-6-chloroisatin is commercially available for example from thesupplier BUTT PARK.

a) 3-Hydroxy-1,3-dihydroindol-2-ones of the formula IV a.15-Bromo-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-one

Formation of the sodium salt of isatin: 2.46 g (51.2 mmol) of sodiumhydride (60% in mineral oil) were added in portions to 12.5 g (51.2mmol) of 5-bromo-6-fluoroisatin in 250 ml of THF at 0° C., and themixture was stirred at 0° C. for one hour.

Formation of the Grignard reagent: ethylmagnesium bromide (61.5 mmol,61.5 ml of a 1M solution in THF) was added dropwise to a solution of2-ethoxy-3-iodopyridine (12.76 g, 51.2 mmol) in 250 ml of THF keepingthe temperature at between 15 and 22° C. The mixture was then stirred atroom temperature for 15 min.

Grignard addition: the solution of the Grignard reagent was pumped intothe ice-cooled solution of the sodium salt of isatin, and the reactionmixture was then stirred at room temperature for three hours. Themixture was poured into 10% ammonium chloride solution and extractedthree times with ethyl acetate. The combined organic phases were washedwith water and saturated brine, dried with magnesium sulfate andconcentrated under reduced pressure. The crystalline precipitate whichhad formed after standing overnight at room temperature was filtered offwith suction and washed with ethyl acetate. 10.0 g of the title compoundwere obtained as a solid.

ESI-MS: 367.00/369.00 [M+H]⁺

a.25-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-one

The title compound was prepared in analogy to example a.1 using5-chloro-6-fluoro-isatin as isatin II.

ESI-MS: 323.05 [M+H]⁺

a.35-Chloro-3-[2-(2,2-difluoroethoxy)phenyl]-6-fluoro-3-hydroxy-1,3-dihydroindol-2-one

The title compound was prepared in analogy to example a.1 using5-chloro-6-fluoro-isatin as isatin II and 2,2-difluoroethoxyiodobenzene(to form the Grignard reagent).

a.45-Chloro-3-(2-ethoxyphenyl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-one

The title compound was prepared in analogy to example a.1 using5-chloro-6-fluoro-isatin as isatin II and ethoxyiodobenzene (to form theGrignard reagent).

a.53-(2-Ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

161 mg (0.14 mmol) of tetrakis(triphenylphosphine)palladium (0) wereadded to a solution of 1.7 g (4.63 mmol) of5-bromo-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-onefrom example a.1 and 544 mg (4.63 mmol) of zinc cyanide in 18 ml ofdimethylformamide (DMF), and the mixture was agitated in a Biotagemicrowave apparatus at 150° C. for 1 h. The reaction solution was workedup by diluting with 300 ml of water, extracting with ethyl acetate (3×)and washing with saturated sodium chloride solution (1×). The combinedorganic phases were dried over magnesium sulfate and filtered, and thesolvent was removed in vacuo. 1.67 g of3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carbonitrilewere obtained.

ESI-MS: 313.10 [M+H]⁺

¹H-NMR (400 MHz, d₆-DMSO): δ [ppm] 7.85 (d, 1H); 7.30 (t, 1H); 7.25 (d,1H); 7.05 (t, 1H); 6.95 (d, 1H); 6.85 (d, 1H); 6.80 (s, 1H); 3.75 (m,2H); 0.95 (t, 3H).

II. Preparation of Compounds of the Formula I II.1 Compounds of theFormula I in which X¹ is NH (Examples 1 to 37) Example 14-(1-Methylpiperidin-4-yl)piperazin-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide1.13-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

0.47 ml (5.81 mmol) of pyridine was added to 1.3 g (4.15 mmol) of3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carbonitrilein 30 ml of dichloromethane. After the reaction mixture had been cooledto 0° C., 0.42 ml (5.81 mmol) of thionyl chloride was added dropwise.The mixture was stirred at room temperature for one hour and then pouredinto ice-water. After stirring for 15 minutes, the organic phase wasseparated off. The aqueous phase was extracted several times withdichloromethane. The combined organic phase was dried over magnesiumsulfate and filtered, and the solvent was removed in vacuo. 1.13 g of3-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrilewere obtained as a solid which was employed without further purificationin the next stage.

ESI-MS: 332.00 [M+H]⁺

1.23-Amino-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

2.4 ml (17.0 mmol) of a 7N methanolic ammonia solution were addeddropwise to a cooled solution of 1.13 g (3.41 mmol) of3-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrilein 20 ml of dichloromethane under a nitrogen atmosphere, and thereaction mixture was then stirred at room temperature overnight. Thereaction mixture was mixed with saturated NaCl solution and extractedwith ethyl acetate (3×). The combined organic phases were dried overmagnesium sulfate and filtered, and the solvent was removed in vacuo.The residue was mixed with 20 ml of diethyl ether. After stirring for 5min, a white solid precipitated and was filtered off and dried in avacuum oven. 800 mg of the title compound were obtained as a whitesolid.

ESI-MS: 313.05 [M+H]⁺

1.33-Amino-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

80 mg (1.68 mmol) of sodium hydride (60% dispersion in mineral oil) wereadded in portions to a solution of 350 mg (1.12 mmol) of3-amino-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrilein 15 ml of anhydrous dimethylformamide under a nitrogen atmosphere andwhile cooling in an ice bath. The mixture was stirred at 0° C. for 10min and then 398 mg (1.68 mmol) of 2,4-dimethoxy-phenylsulfonyl chloridewere added, and the mixture was stirred at room temperature for 15 min.The reaction mixture was poured into ice-water and then extracted withethyl acetate. The organic phase was washed with saturated sodiumchloride solution and dried over magnesium sulfate, and the solvent wasevaporated. The residue was purified by chromatography on silica gel(Redisep cartridge, mobile phase gradient from 0 to 3% methanol in ethylacetate). 236 mg of the title compound were obtained as a white solid.

ESI-MS: 513.15 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.25 (d, 1H); 8.10 (m, 1H); 7.95 (d,1H); 7.75 (d, 1H); 7.45 (d, 1H); 7.10 (m, 1H); 6.75 (m, 2H); 4.00 (m,2H); 3.90 (s, 3H); 3.75 (s, 3H); 3.40 (m, 2H); 0.85 (t, 3H).

1.4 Phenyl[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate

61 μl (0.49 mmol) of phenyl chloroformate were slowly added dropwise toa solution, cooled to 0° C., of 226 mg (0.44 mmol) of3-amino-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrilein 4 ml of pyridine. After 5 minutes, the solvent was evaporated. Theresidue was mixed with 20 ml of water and extracted with diethyl ether(2×). The organic phase was washed with water and saturated sodiumchloride solution, dried over magnesium sulfate and concentrated underreduced pressure. The residue was purified by chromatography on silicagel (Redisep cartridge, mobile phase gradient from 0 to 5% methanol inethyl acetate). 200 mg of the title compound were obtained.

ESI-MS: 633.15 [M+H]⁺

1.54-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

A mixture of 50 mg (0.07 mmol) of phenyl[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate,26 mg (0.14 mmol) of 1-(1-methylpiperidin-4-yl)piperazine and 5 ml ofdried THF was stirred at room temperature for 2 hours. The reactionmixture was diluted with dichloromethane and washed with water andsaturated sodium chloride solution, and the organic phase was dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by chromatography on silica gel (Redisep cartridge, mobilephase gradient from 0 to 20% methanol in dichloromethane). 27 mg of thetitle compound were obtained as a white solid.

ESI-MS: 722.25 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.15 (m, 1H); 7.85 (d, 1H); 7.80 (d,1H); 7.70 (m, 2H); 7.65 (s, 1H); 7.05 (m, 1H); 6.70 (m, 2H); 4.15 (m,2H); 3.85 (s, 3H); 3.50 (s, 3H); 3.20 (m, 4H); 2.80 (m, 2H); 2.35 (m,4H); 2.15 (m, 4H); 1.85 (m, 2H); 1.65 (m, 2H); 1.40 (m, 2H); 1.10 (t,3H).

Racemate Resolution of Compounds of the Formula I

Racemic compounds of the formula I can be resolved for example byseparation on a preparative chiral column, e.g. Chiracel OD.

The rotations were determined at a wavelength of 589 nm at 22° C. inchloroform as solvent and a concentration of 1 mg/ml test substance.

Example 1A and Example 1B Racemate resolution of4-(1-methylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

4-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamidefrom example 1 was separated on a chiral preparative column (ChiralcelOD, flow rate 45 ml/min) with heptane:ethanol:tert-butanol in the ratio14:6:1 as eluent. The enantiomer (example 1A) with positive rotation(rotation determined in chloroform) and the enantiomer (example 1B) withnegative rotation (rotation determined in chloroform) were obtained.

Example 1A(+)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamideα (CHCl₃): plus rotation

ESI-MS: 722.25 [M+H]⁺

Example 1B(−)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamideα (CHCl₃): minus rotation

ESI-MS: 722.25 [M+H]⁺

Examples 2 to 37

The compounds of the formula I according to examples 2 to 37 wereprepared in analogy to example 1 using the appropriate isatins II,sulfonyl chlorides VII and amines X.

The compounds I of the invention in which X¹ is NH can also be purifiedby crystallization and/or by preparative HPLC (RP, eluentsacetonitrile/water, 0.1% TFA or 0.1% acetic acid). Compounds I thenresult where appropriate as trifluoroacetic acid salt,bis(trifluoroacetic acid) salt or acetic acid salt.

Example 24-(1-Ethylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 736.15 [M+H]⁺

Example 34-(4-Methylpiperazin-1-yl)piperidine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 722.25 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.15 (m, 1H); 7.90 (d, 1H); 7.80 (d,1H); 7.70 (m, 2H); 7.65 (s, 1H); 7.05 (m, 1H); 6.70 (m, 2H); 4.20 (m,2H); 3.85 (s, 3H); 3.80 (m, 2H); 3.50 (s, 3H); 2.65 (m, 2H); 2.45-2.25(m, 9H); 2.15 (s, 3H); 1.60 (m, 2); 1.15 (m, 5H).

Example 44-(4-Ethylpiperazin-1-yl)piperidine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 736.20 [M+H]⁺

Example 54-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide5.13-Amino-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

The title compound was prepared using3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carbonitrileas 3-hydroxy-1,3-dihydroindol-2-one IV and 4-methoxyphenylsulfonylchloride as sulfonyl chloride VII in analogy to example 1.1 to 1.3.

ESI-MS: 483.10 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.25 (d, 1H); 8.15 (d, 2H); 8.10 (m,1H); 7.90 (d, 1H); 7.45 (d, 1H); 7.25 (d, 2H); 7.15 (m, 1H); 3.95 (m,1H); 3.90 (s, 3H); 3.55 (m, 1H); 3.05 (m, 2H); 0.55 (t, 3H).

5.2 Phenyl[5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate

Preparation took place in analogy to example 1.4.

ESI-MS: 603.15 [M+H]⁺

5.34-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

Preparation took place in analogy to example 1.5.

ESI-MS: 692.20 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): 5 [ppm] 8.15 (m, 1H); 8.00 (d, 2H); 7.95 (d,1H); 7.75 (d, 1H); 7.65 (m, 2H); 7.15 (d, 2H); 7.05 (m, 1H); 4.10 (m,1H); 4.05 (m, 1H); 3.85 (s, 3H); 3.75 (m, 2H); 2.60 (m, 2H); 2.45 (m,4H); 2.30 (m, 4H); 2.15 (m, 4H); 1.65 (m, 2H); 1.15 (m, 2H); 1.05 (t,3H).

Example 64-(1-Ethylpiperidin-4-yl)piperazine-1-[5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 706.25 [M+H]⁺

Example 74-(4-Methylpiperazin-1-yl)piperidine-1-[5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 692.15 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.15 (m, 1H); 8.05 (d, 2H); 8.00 (d,1H); 7.75 (d, 1H); 7.70 (s, 1H); 7.65 (m, 1H); 7.15 (d, 2H); 7.05 (m,1H); 4.10 (m, 1H); 4.05 (m, 1H); 3.85 (s, 3H); 3.20 (m, 4H); 2.80 (m,4H); 2.35 (m, 2H); 2.15 (m, 4H); 1.90 (m, 2H); 1.65 (m, 2H); 1.40 (m,2H); 1.05 (t, 3H).

Example 84-(4-Ethylpiperazin-1-yl)piperidine-1-[5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 706.15 [M+H]⁺

Example 94-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamideas trifluoro-acetic acid salt

ESI-MS: 721.20 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 10.35 (bs, 1H); 8.00 (s, 1H); 7.90(d, 1H); 7.75 (m, 2H); 7.45 (d, 1H); 7.35 (t, 1H); 7.00 (m, 2H); 6.70(m, 2H); 4.05 (m, 1H); 3.90 (m, 4H); 3.65-3.40 (m, 9H); 3.30-2.95 (m,7H); 2.80 (s, 3H); 2.30 (m, 2H); 1.90 (m, 2H); 1.15 (t, 3H).

Example 104-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-3-(2-ethoxyphenyl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamideas trifluoro-acetic acid salt

ESI-MS: 691.20 [M+H]⁺

¹H-NMR (500 MHz, CH₃OD): δ [ppm] 8.05 (d, 2H); 7.85 (d, 1H); 7.55 (d,1H); 7.45 (d, 1H); 7.35 (t, 1H); 7.10 (d, 2H); 7.05 (t, 1H); 7.00 (d,1H); 4.05 (m, 1H); 3.95 (m, 1H); 3.90 (s, 3H); 3.70 (m, 2H); 3.60 (m,4H); 3.45 (m, 1H); 3.25 (m, 4H); 3.15 (m, 2H); 2.95 (s, 3H); 2.40 (m,2H); 2.10 (m, 2H); 1.25 (t, 3H).

Example 114-(1-Ethylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 7.90 (d, 1H); 7.70 (m, 2H); 7.60 (s,1H); 7.35 (m, 2H); 6.95 (m, 2H); 6.70 (m, 2H); 4.05 (m, 1H); 3.90 (m,4H); 3.50 (bs, 3H); 3.20 (m, 4H); 3.00 (m, 2H); 2.45 (m, 2H); 2.35 (m,4H); 2.20 (m, 1H); 2.05 (m, 2H); 1.75 (m, 2H); 1.45 (m, 2H); 1.15 (t,3H); 1.05 (t, 3H).

Example 124-(1-Ethylpiperidin-4-yl)piperazine-1-[5-cyano-3-(2-ethoxyphenyl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamideas trifluoroacetic acid salt

ESI-MS: 705.20 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 10.05 (bs, 1H); 8.05 (m, 3H); 7.75(d, 1H); 7.65 (m, 2H); 7.35 (t, 1H); 7.15 (d, 2H); 7.00 (t, 1H); 6.95(d, 1H); 3.95-2.90 (m, 20H); 2.30 (m, 2H); 1.90 (m, 2H); 1.25 (t, 3H);1.10 (t, 3H).

Example 134-(1-Ethylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-5-cyano-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamideas trifluoroacetic acid salt

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 10.10 (bs, 1H); 8.10 (d, 2H); 8.05(s, 1H); 7.80 (m, 2H); 7.65 (m, 4H); 7.35 (t, 1H); 7.05 (t, 1H); 6.95(d, 1H); 3.95-3.75 (m, 3H); 3.65 (m, 3H); 3.45-2.90 (m, 11H); 2.30 (m,2H); 1.95 (m, 2H); 1.25 (t, 3H); 1.10 (t, 3H).

Example 144-(4-Methylpiperazin-1-yl)piperidine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamideas trifluoroacetic acid salt

ESI-MS: 721.20 [M+H]⁺

¹H-NMR (500 MHz, CH₃OD): δ [ppm] 8.00 (d, 1H); 7.85 (d, 1H); 7.65 (d,1H); 7.35 (t, 1H); 7.25 (d, 1H); 7.00 (d, 1H); 6.95 (t, 1H); 6.65 (d,1H); 6.60 (s, 1H); 4.15 (m, 1H); 4.05 (m, 3H); 3.90 (s, 3H); 3.65 (m,4H); 3.55 (m, 6H); 3.35 (m, 2H); 2.95 (s, 3H); 2.80 (m, 2H); 2.05 (m,2H); 1.55 (m, 2H); 1.30 (t, 3H).

Example 154-(4-Methylpiperazin-1-yl)piperidine-1-[5-cyano-3-(2-ethoxyphenyl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamideas trifluoroacetic acid salt

ESI-MS: 691.20 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.00 (d, 2H); 7.75 (m, 2H); 7.60 (m,2H); 7.35 (t, 1H); 7.15 (d, 2H); 7.00 (t, 1H); 6.95 (d, 1H); 3.95-3.80(m, 7H); 3.55-3.05 (m, 8H); 2.85 (m, 4H); 2.60 (m, 2H); 1.90 (m, 2H);1.30 (m, 2H); 1.10 (t, 3H).

Example 164-(4-Ethylpiperazin-1-yl)piperidine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamideas trifluoroacetic acid salt

ESI-MS: 735.25 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 7.90 (d, 1H); 7.75 (m, 3H); 7.40 (d,1H); 7.35 (t, 1H); 6.95 (m, 2H); 6.70 (m, 2H); 4.05 (m, 1H); 3.95-3.85(m, 6H); 3.55-2.95 (m, 14H); 2.65 (m, 2H); 1.85 (m, 2H); 1.30 (m, 2H);1.20 (m, 6H).

Example 174-(4-Ethylpiperazin-1-yl)piperidine-1-[5-cyano-3-(2-ethoxyphenyl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamideas trifluoroacetic acid salt

ESI-MS: 705.20 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.00 (d, 2H); 7.80 (s, 1H); 7.75 (d,1H); 7.60 (m, 2H); 7.35 (t, 1H); 7.15 (d, 2H); 7.00 (t, 1H); 6.95 (d,1H); 3.95-3.80 (m, 7H); 3.70-3.15 (m, 11H); 2.65 (m, 2H); 1.95 (m, 2H);1.35 (m, 2H); 1.25 (t, 3H); 1.10 (t, 3H).

Example 184-(4-Ethylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-5-cyano-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamideas trifluoroacetic acid salt

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.10 (d, 2H); 7.85 (s, 1H); 7.80 (m,2H); 7.65 (m, 4H); 7.35 (t, 1H); 7.00 (t, 1H); 6.95 (d, 1H); 4.25 (m,2H); 3.95 (m, 2H); 3.85 (m, 2H); 3.70-3.15 (m, 11H); 2.65 (m, 2H); 1.95(m, 2H); 1.35 (m, 2H); 1.25 (t, 3H); 1.10 (t, 3H).

Example 194-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide19.13-Amino-5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-1,3-dihydroindol-2-one

3-Amino-5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-1,3-dihydroindol-2-onewas prepared in analogy to example 1.1 to 1.3 using5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-oneas 3-hydroxy-1,3-dihydroindol-2-one IV and 2,4-dimethoxyphenylsulfonylchloride as sulfonyl chloride VII.5-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-onewas prepared in analogy to example a.1.

ESI-MS: 522.10 [M+H]⁺

19.2 Phenyl[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate

The title compound was prepared in analogy to example 1.4.

ESI-MS: 642.10 [M+H]⁺

19.34-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

The title compound was prepared in analogy to example 1.5.

ESI-MS: 731.20 [M+H]⁺

Example 204-(1-Methylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide20.13-Amino-1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-1,3-dihydro-indol-2-one

The title compound was prepared in analogy to example 1.1 to 1.3 using5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-oneas 3-hydroxy-1,3-dihydroindol-2-one IV and phenylsulfonyl chloride assulfonyl chloride VII.5-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-onewas prepared in analogy to example a.1.

ESI-MS: 462.00 [M+H]⁺

20.2 Phenyl[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate

The title compound was prepared in analogy to example 1.4.

ESI-MS: 582.00 [M+H]⁺

20.34-(1-Methylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

The title compound was prepared in analogy to example 1.5.

ESI-MS: 671.05 [M+H]⁺

Example 214-(1-Ethylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.15 (m, 1H); 7.90 (d, 1H); 7.65 (m,2H); 7.60 (s, 1H); 7.50 (d, 1H); 7.00 (m, 1H); 6.70 (m, 2H); 4.20 (m,2H); 3.85 (s, 3H); 3.50 (s, 3H); 3.25 (m, 4H); 2.90 (m, 2H); 2.35 (m,6H); 2.15 (m, 1H); 1.85 (m, 2H); 1.65 (m, 2H); 1.35 (m, 2H); 1.15 (t,3H); 0.95 (t, 3H).

Example 224-(1-Ethylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 685.20 [M+H]⁺

Example 234-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 731.20 [M+H]⁺

Example 244-(4-Methylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 671.10 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.15 (m, 1H); 8.10 (d, 2H); 7.90 (d,1H); 7.80-7.60 (m, 5H); 7.40 (d, 1H); 7.05 (m, 1H); 4.15 (m, 1H); 4.05(m, 1H); 3.80 (m, 2H); 2.60 (m, 2H); 2.50-2.25 (m, 9H); 2.20 (s, 3H);1.65 (m, 2H); 1.15 (m, 2H); 1.05 (t, 3H).

Example 254-(4-Ethylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 685.20 [M+H]⁺

Example 261′-Methyl[4,4′]bipiperidinyl-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-pyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS:

Example 271′-Ethyl[4,4]bipiperidinyl-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-pyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 744.15 [M+H]⁺

Example 284-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-3-[2-(2,2-difluoroethoxy)phenyl]-1-(2,4-dimethoxyphenylsulfonyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 766.20 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.00 (d, 1H); 7.75 (m, 2H); 7.65 (s,1H); 7.45 (m, 1H); 7.20 (d, 1H); 7.05 (d, 1H); 7.00 (t, 1H); 6.80 (m,2H); 6.45 (t, J=70 Hz, 1H); 4.55 (m, 1H); 4.40 (m, 1H); 3.95 (s, 3H);3.90 (m, 2H); 3.55 (s, 3H); 2.70 (m, 2H); 2.55 (m, 4H); 2.40 (m, 5H);2.20 (s, 3H); 1.70 (m, 2H); 1.25 (m, 2H).

Example 294-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-3-[2-(2,2-difluoroethoxy)phenyl]-1-(2,4-dimethoxyphenylsulfonyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 766.20 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 7.95 (d, 1H); 7.65 (m, 2H); 7.60 (s,1H); 7.35 (t, 1H); 7.10 (d, 1H); 6.95 (m, 1H); 6.90 (t, 1H); 6.75 (d,1H); 6.70 (m, 1H); 6.35 (t, J=70 Hz, 1H); 4.45 (m, 1H); 4.30 (m, 1H);3.85 (s, 3H); 3.45 (s, 3H); 3.20 (m, 4H); 2.75 (m, 2H); 2.35 (m, 4H);2.15 (m, 4H); 1.85 (m, 2H); 1.65 (m, 2H); 1.40 (m, 2H).

Example 301′-Methyl[4,4′]bipiperidinyl-1-[5-chloro-3-[2-(2,2-difluoroethoxy)phenyl]-1-(2,4-dimethoxyphenylsulfonyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 765.20 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 7.90 (d, 1H); 7.65 (m, 2H); 7.55 (s,1H); 7.35 (t, 1H); 7.10 (d, 1H); 6.95 (m, 1H); 6.90 (t, 1H); 6.75 (d,1H); 6.70 (s, 1H); 6.35 (t, J=70 Hz, 1H); 4.45 (m, 1H); 4.30 (m, 1H);3.90 (s, 3H); 3.85 (m, 2H); 3.45 (s, 3H); 2.80 (m, 2H); 2.55 (m, 2H);2.15 (s, 3H); 1.85 (m, 2H); 1.55 (m, 4H); 1.15 (m, 3H), 0.95 (m, 3H).

Example 314-(1-Methylpiperidin-4-yl)piperazine-1-[1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-pyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamideas trifluoro-acetic acid salt

ESI-MS: 715.20 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.05 (m, 2H); 7.85 (m, 1H); 7.25 (t,1H); 7.10 (m, 2H); 6.75 (m, 1H); 6.60 (d, 1H); 6.40 (s, 1H); 4.55 (m,2H); 3.85 (s, 3H); 3.75-3.50 (m, 10H); 3.10 (m, 4H); 2.90 (m, 2H); 2.80(s, 3H); 2.45 (m, 4H); 2.15 (m, 2H); 1.45 (t, 3H).

Example 324-(1-Methylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 655.20 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.10 (m, 3H); 7.80 (m, 1H); 7.65 (m,1H); 7.50 (m, 2H); 7.20 (d, 1H); 7.15 (t, 1H); 6.80 (m, 1H); 6.70 (s,1H); 4.55 (m, 2H); 3.20 (m, 4H); 2.90 (m, 2H); 2.45 (m, 4H); 2.25 (m,4H); 1.95 (m, 2H); 1.75 (m, 2H); 1.60 (m, 2H); 1.45 (t, 3H).

Example 334-(1-Ethylpiperidin-4-yl)piperazine-1-[1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-pyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 729.30 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.10 (m, 1H); 7.90 (d, 1H); 7.75 (m,2H); 7.70 (s, 1H); 7.35 (t, 1H); 7.00 (m, 1H); 6.70 (d, 1H); 6.65 (m,1H); 4.20 (m, 2H); 3.85 (s, 3H); 3.50 (s, 3H); 3.20 (m, 4H); 2.90 (m,2H); 2.35 (m, 6H); 2.15 (m, 1H); 1.85 (m, 2H); 1.70 (m, 2H); 1.35 (m,2H); 1.10 (t, 3H); 0.95 (t, 3H).

Example 344-(1-Ethylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 669.20 [M+H]⁺

Example 354-(4-Methylpiperazin-1-yl)piperidine-1-[1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-pyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamideas trifluoro-acetic acid salt

ESI-MS: 715.20 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.05 (m, 2H); 7.80 (m, 1H); 7.25 (t,1H); 7.00 (m, 2H); 6.75 (m, 1H); 6.60 (d, 1H); 6.40 (s, 1H); 4.50 (m,2H); 3.95 (m, 2H); 3.85 (s, 3H); 3.60 (m, 8H); 3.55 (s, 3H); 3.25 (m,1H); 3.35 (s, 3H); 2.25 (m, 2H); 2.00 (m, 2H); 1.60 (m, 2H); 1.45 (t,3H).

Example 364-(4-Methylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide

ESI-MS: 655.20 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.10 (m, 3H); 7.80 (m, 1H); 7.65 (m,1H); 7.55 (m, 2H); 7.30 (d, 1H); 7.25 (t, 1H); 6.80 (m, 1H); 6.70 (s,1H); 4.55 (m, 2H); 3.75 (m, 2H); 2.70 (m, 2H); 2.60-2.40 (m, 8H); 2.35(m, 1H); 2.30 (s, 3H); 1.75 (m, 2H); 1.45 (t, 3H); 1.35 (m, 2H).

Example 374-(4-Ethylpiperazin-1-yl)piperidine-1-[1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-pyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamideas trifluoro-acetic acid salt

ESI-MS: 729.20 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.15 (m, 1H); 7.90 (d, 1H); 7.70 (s,1H); 7.65 (m, 1H); 7.60 (d, 1H); 7.35 (t, 1H); 7.00 (m, 1H); 6.70 (m,2H); 4.20 (m, 2H); 3.95 (m, 2H); 3.85 (s, 3H); 3.55-2.85 (m, 14H); 2.65(m, 2H); 1.85 (m, 2H); 1.30 (m, 2H); 1.20 (t, 3H); 1.15 (t, 3H).

II.2 Compounds of the Formula I in which X¹ is O (Examples 38 to 55)Example 385-Cyano-1-(2,4-dimethoxybenzenesulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 38.1 Phenyl5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-3-phenoxycarbonyloxy-2,3-dihydroindole-1-carboxylate

330 μl (2.62 mmol) of phenyl chloroformate were slowly added dropwise toa solution, cooled to 0° C., of 342 mg (0.66 mmol; 60% purity) of3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile(mother liquor from example a.2) in 8 ml of pyridine, and the reactionmixture was stirred at room temperature overnight. The reaction mixturewas diluted with dichloromethane and extracted with water. The organicphase was washed with water and saturated sodium chloride solution,dried over magnesium sulfate and concentrated under reduced pressure.The residue was purified by chromatography on silica gel (Redisepcartridge, mobile phase gradient from 0 to 5% methanol indichloromethane). 291 mg of the title compound were obtained.

ESI-MS: 554.15 [M+H]⁺

38.25-Cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

A mixture of 291 mg (0.53 mmol) of phenyl5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-3-phenoxycarbonyloxy-2,3-dihydroindole-1-carboxylate,289 mg (1.58 mmol) of 1-(1-methylpiperidin-4-yl)piperazine and 6 ml ofdried tetrahydrofuran (THF) was stirred at room temperature overnight.The reaction mixture was concentrated under reduced pressure and stirredwith methanol. The precipitated solid was filtered off and dried in avacuum drying oven. 158 mg of the title compound were obtained as awhite solid.

ESI-MS: 523.20 [M+H]⁺

38.35-Cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

9.2 mg (0.19 mmol) of sodium hydride (50% dispersion in mineral oil)were added to a solution of 50 mg (0.10 mmol) of5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate in 2 ml of anhydrousdimethylformamide under a nitrogen atmosphere and while cooling in anice bath. The mixture was stirred at 0° C. for 10 min and then 29 mg(0.12 mmol) of 2,4-dimethoxyphenylsulfonyl chloride were added, andstirring was continued at room temperature for 30 min. The reactionmixture was poured into ice-water and then extracted with ethyl acetate.The organic phase was washed with saturated sodium chloride solution anddried over magnesium sulfate, and the solvent was evaporated. Theresidue was purified by chromatography on silica gel (Redisep cartridge,mobile phase gradient from 0 to 20% methanol in dichloromethane). 34 mgof the title compound were obtained as a white solid.

ESI-MS: 723.25 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.15 (m, 2H); 7.90 (d, 1H); 7.85 (m,2H); 7.15 (m, 1H); 6.70 (m, 2H); 4.15 (m, 2H); 3.85 (s, 3H); 3.55 (s,3H); 3.05 (m, 2H); 2.80 (m, 2H); 2.45 (m, 2H); 2.30 (m, 2H); 2.15 (m,4H); 1.90 (m, 2H); 1.65 (m, 2H); 1.40 (m, 2H); 1.05 (t, 3H).

Examples 39 to 55

The compounds of the formula I in which X¹ is O according to examples 39to 55 were prepared in analogy to example 38 using the appropriate3-hydroxy-1,3-dihydroindol-2-ones of the formula IV, sulfonyl chloridesVII and amines X.

Example 395-Cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 693.25 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.15 (m, 1H); 8.05 (d, 2H); 7.95 (d,1H); 7.90 (d, 1H); 7.20 (d, 1H); 7.00 (m, 3H); 4.25 (m, 2H); 3.85 (s,3H); 3.55 (m, 2H); 3.10 (m, 1H); 3.05 (m, 1H); 2.95 (m, 2H); 2.60 (m,1H); 2.50 (m, 1H); 2.40 (m, 2H); 2.30 (m, 4H); 2.05 (m, 2H); 1.75 (m,2H); 1.65 (m, 2H); 1.20 (t, 3H).

Example 401-Phenylsulfonyl-5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 663.25 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.15 (m, 1H); 8.10 (d, 2H); 7.90 (d,1H); 7.85 (d, 1H); 7.70 (m, 2H); 7.60 (m, 1H); 7.30 (m, 1H); 7.15 (m,1H); 4.10 (m, 1H); 3.95 (m, 1H); 3.60 (m, 2H); 3.30 (m, 2H); 3.00 (m,2H); 2.75 (m, 1H); 2.65 (s, 3H); 2.45 (m, 3H); 2.35 (m, 2H); 1.85 (m,2H); 1.65 (m, 2H); 0.95 (t, 3H).

Example 415-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 41.1 Phenyl5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-3-phenoxycarbonyloxy-2,3-dihydroindole-1-carboxylate

ESI-MS: 563.10 [M+H]⁺

41.25-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS:

41.35-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 732.25 [M+H]⁺

¹H-NMR (400 MHz, CH₃OD): δ [ppm] 8.15 (m, 2H); 7.95 (d, 1H); 7.85 (d,1H); 7.20 (d, 1H); 7.10 (t, 1H); 6.65 (m, 2H); 4.25 (m, 2H); 3.90 (s,3H); 3.65 (m, 5H); 3.20 (m, 2H); 2.95 (m, 2H); 2.60 (m, 2H); 2.45 (m,2H); 2.30 (m, 4H); 2.05 (m, 2H); 1.85 (m, 2H); 1.55 (m, 2H); 1.20 (t,3H).

Example 425-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 702.20 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.15 (m, 1H); 8.05 (m, 2H); 7.95 (d,1H); 7.85 (d, 1H); 6.95 (m, 4H); 4.25 (m, 2H); 3.85 (s, 3H); 3.55 (m,2H); 3.10 (m, 2H); 2.90 (m, 2H); 2.65-2.35 (m, 4H); 2.25 (m, 4H); 1.95(m, 2H); 1.75 (m, 2H); 1.55 (m, 2H); 1.25 t, 3H).

Example 435-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 702.15 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ[ppm] 8.15 (m, 2H); 7.90 (m, 2H); 7.55 (t,1H); 7.05 (t, 1H); 7.00 (d, 1H); 6.95 (m, 2H); 4.30 (m, 2H); 3.65 (s,3H); 3.55 (m, 2H); 3.10 (m, 2H); 2.90 (m, 2H); 2.60-2.20 (m, 8H); 1.90(m, 2H); 1.70 (m, 2H); 1.55 (m, 2H); 1.25 (m, 3H).

Example 445-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxy-2-trifluoromethoxyphenyl-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 786.15 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.20 (d, 1H); 8.15 (m, 1H); 7.90 (m,2H); 6.95 (m, 2H); 6.85 (m, 2H); 4.25 (m, 2H); 3.85 (s, 3H); 3.55 (m,2H); 3.20-2.85 (m, 4H); 2.60-2.35 (m, 4H); 2.35 (m, 4H); 1.95 (m, 2H);1.70 (m, 2H); 1.60 (m, 2H); 1.25 (t, 3H).

Example 451-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 672.25 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.15 (m, 1H); 8.10 (d, 2H); 7.80 (m,1H); 7.65 (m, 3H); 7.45 (d, 1H); 7.30 (m, 1H); 7.15 (m, 1H); 4.10 (m,1H); 3.95 (m, 1H); 3.60 (m, 2H); 3.20 (m, 2H); 3.00 (m, 2H); 2.85 (m,2H); 2.65 (s, 3H); 2.45 (m, 3H); 2.30 (m, 2H); 1.85 (m, 2H); 1.65 (m,2H); 0.95 (t, 3H).

Example 466-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 46.1 Phenyl6-chloro-3-(2-ethoxypyridin-3-yl)-5-fluoro-2-oxo-3-phenoxycarbonyloxy-2,3-dihydroindole-1-carboxylate

ESI-MS: 563.50 [M+H]⁺

46.26-Chloro-3-(2-ethoxypyridin-3-yl)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 532.20 [M+H]⁺

46.36-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 732.20 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.10 (m, 2H); 8.05 (d, 1H); 7.90 (d,1H); 6.95 (m, 1H); 6.80 (d, 1H); 6.55 (d, 1H); 6.40 (s, 1H); 4.25 (m,2H); 3.85 (s, 3H); 3.60 (s, 3H); 3.55 (m, 2H); 3.15 (m, 2H); 2.90 (m,2H); 2.60-2.35 (m, 4H); 2.25 (m, 4H); 1.95 (m, 2H); 1.70 (m, 2H); 1.55(m, 2H); 1.25 (t, 3H).

Example 476-Chloro-3-(2-ethoxypyridin-3-yl)-5-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 702.20 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.15 (m, 1H); 8.05 (m, 3H); 7.90 (d,1H); 6.95 (m, 3H); 6.80 (d, 1H); 4.25 (m, 2H); 3.85 (s, 3H); 3.55 (m,2H); 3.10 (m, 2H); 2.90 (m, 2H); 2.65-2.35 (m, 4H); 2.25 (m, 4H); 1.95(m, 2H); 1.75 (m, 2H); 1.55 (m, 2H); 1.25 (t, 3H).

Example 486-Chloro-3-(2-ethoxypyridin-3-yl)-5-fluoro-1-(4-methoxy-2-trifluoromethoxyphenyl-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 786.15 [M+H]⁺

¹H-NMR (500 MHz, MeOD): δ [ppm] 8.15 (d, 1H); 8.10 (m, 2H); 8.05 (d,1H); 7.05 (m, 3H); 6.95 (s, 1H); 4.25 (m, 2H); 3.90 (s, 3H); 3.60 (m,2H); 3.10 (m, 2H); 2.90 (m, 2H); 2.55 (m, 2H); 2.40 (m, 2H); 2.25 (m,4H); 2.00 (m, 2H); 1.80 (m, 2H); 1.55 (m, 2H); 1.20 (t, 3H).

Example 491-Phenylsulfonyl-6-chloro-3-(2-ethoxypyridin-3-yl)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 672.20 [M+H]⁺

¹H-NMR (400 MHz, CDCl₃): δ [ppm] 8.15 (m, 3H); 8.05 (d, 1H); 7.90 (d,1H); 7.85 (d, 1H); 7.65 (t, 1H); 7.55 (m, 2H); 6.95 (m, 1H); 6.75 (d,1H); 4.25 (m, 2H); 3.55 (m, 2H); 3.00 (m, 4H); 2.60-2.25 (m, 8H); 2.05(m, 2H); 1.75 (m, 2H); 1.65 (m, 2H); 1.25 (t, 3H).

Example 506-Chloro-3-(2-ethoxypyridin-3-yl)-5-fluoro-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 702.20 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.15 (m, 3H); 7.90 (d, 1H); 7.55 (t,1H); 7.05 (t, 1H); 6.95 (m, 2H); 6.80 (d, 1H); 4.30 (m, 2H); 3.65 (s,3H); 3.55 (m, 2H); 3.10 (m, 2H); 2.90 (m, 2H); 2.60-2.20 (m, 8H); 1.90(m, 2H); 1.70 (m, 2H); 1.55 (m, 2H); 1.25 (m, 3H).

Example 511-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 51.13-(2-Ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 516.25 [M+H]⁺

51.21-(2,4-Dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 716.30 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.15 (m, 1H); 8.05 (d, 1H); 7.95 (m,2H); 6.95 (m, 1H); 6.85 (t, 1H); 6.55 (d, 1H); 6.40 (s, 1H); 4.30 (m,2H); 3.85 (s, 3H); 3.65 (s, 3H); 3.55 (m, 2H); 3.15 (m, 2H); 2.90 (m,2H); 2.65-2.35 (m, 4H); 2.25 (m, 4H); 1.95 (m, 2H); 1.75 (m, 2H); 1.55(m, 2H); 1.25 (m, 3H).

Example 523-(2-Ethoxypyridin-3-yl)-5,6-difluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 686.20 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.15 (m, 1H); 8.05 (d, 2H); 7.90 (d,1H); 7.85 (m, 1H); 6.95 (m, 3H); 6.80 (t, 1H); 4.25 (m, 2H); 3.85 (s,3H); 3.55 (m, 2H); 3.20-3.00 (m, 2H); 2.90 (m, 2H); 2.65-2.35 (m, 4H);2.25 (m, 4H); 1.95 (m, 2H); 1.75 (m, 2H); 1.55 (m, 2H); 1.25 (m, 3H).

Example 533-(2-Ethoxypyridin-3-yl)-5,6-difluoro-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 686.20 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.15 (m, 2H); 7.95 (m, 1H); 7.90 (d,1H); 7.55 (t, 1H); 7.05 (t, 1H); 6.95 (m, 2H); 6.85 (t, 1H); 4.30 (m,2H); 3.65 (s, 3H); 3.55 (m, 2H); 3.10 (m, 2H); 2.90 (m, 2H); 2.65-2.20(m, 8H); 1.95 (m, 2H); 1.75 (m, 2H); 1.55 (m, 2H); 1.30 (m, 3H).

Example 543-(2-Ethoxypyridin-3-yl)-5,6-difluoro-1-(4-methoxy-2-trifluoromethoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 770.20 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.25 (d, 1H); 8.15 (m, 1H); 7.90 (m,2H); 6.95 (m, 1H); 6.85 (m, 3H); 4.25 (m, 2H); 3.85 (s, 3H); 3.55 (m,2H); 3.20-2.90 (m, 4H); 2.65-2.35 (m, 4H); 2.30 (m, 4H); 1.95 (m, 2H);1.70 (m, 2H); 1.55 (m, 2H); 1.25 (m, 3H).

Example 551-Phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS: 656.25 [M+H]⁺

¹H-NMR (500 MHz, CDCl₃): δ [ppm] 8.15 (m, 3H); 7.90 (m, 1H); 7.85 (m,1H); 7.65 (m, 1H); 7.55 (m, 2H); 6.95 (m, 1H); 6.80 (t, 1H); 4.20 (m,2H); 3.55 (m, 2H); 3.10-2.95 (m, 4H); 2.55 (m, 1H); 2.50 (m, 1H); 2.35(m, 2H); 2.30 (m, 4H); 2.05 (m, 2H); 1.75 (m, 2H); 1.65 (m, 2H); 1.20(t, 3H).

II.3 Compounds of the Formula I in which X¹ is CH₂ Example 56(+)-5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydroindol-2-oneas trifluoro-acetic acid salt 56.1 Dimethyl2-[5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]malonate

7.26 ml (63.5 mmol) of dimethyl malonate were slowly added dropwise to asuspension, cooled to 10° C., of 2.311 g (57.8 mmol, 60% w/w) of sodiumhydride in 150 ml of dimethylformamide. The reaction mixture was thenstirred at room temperature for 30 minutes and subsequently 6.57 g(19.26 mmol) of3,5-dichloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-1,3-dihydroindol-2-one(prepared using5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-onein analogy to example 1.1) was added in portions undiluted. The reactionmixture was then stirred for a further 15 minutes at room temperature.The progress of the reaction was monitored by thin-layer chromatography(silica gel, heptane/ethyl acetate 1:1). The mixture was worked up bystirring into cold 1N HCl and adding dichloromethane. The phases wereseparated, and the aqueous phase was extracted with dichloromethane(1×). The combined organic phase was washed initially with water (1×)and then with saturated sodium chloride solution (1×), dried overmagnesium sulfate and filtered, and the solvent was removed in vacuo.The residue was again partly dissolved in a little dichloromethane, andpentane was added. Several fractions of crystals were obtained. Intotal, 3.23 g of the title compound were obtained as a white solid and1.62 g as a beige-colored solid.

ESI-MS: 437.10 [M+H]⁺

56.2 Methyl[5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]-acetate

50 ml of 2N sodium hydroxide solution were added to a solution of 4.85 g(11.10 mmol) of dimethyl2-[5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]malonatein 5 ml of ethanol, and the mixture was stirred at room temperature for1 hour. Precursor was no longer detectable after this by a TLC check(silica gel, heptane/ethyl acetate 1:1). The reaction mixture wasstirred into ice-cold 1N hydrochloric acid and mixed withdichloromethane. The phases were separated and the aqueous phase wasextracted once with dichloromethane. The combined organic phase waswashed initially with water (1×) and then with saturated sodium chloridesolution (1×), dried over magnesium sulfate and filtered, and thesolvent was removed in vacuo. The resulting solid, monomethyl2-[5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]malonate(4.58 g), was dried in a vacuum drying oven at 40° C.

ESI-MS: 423.10 [M+H]⁺

The resulting monomethyl2-[5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]malonate(4.58 g) was heated in a one-neck flask under a blanket of nitrogen to150° C. During this, CO₂ gas was evolved and methyl[5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]acetatewas formed. The reaction mixture was cooled to room temperature, and thesubstance was mixed with methanol. The crystals which formed were storedin a refrigerator at 5° C. overnight. The solid was filtered off withsuction and washed with a little methanol. 3.286 g (8.68 mmol, 80%yield) of the title compound were obtained as a white solid.

ESI-MS: 379.05 [M+H]⁺

56.35-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]aceticacid

Firstly 5 ml of water and then 2.3 ml of a 50% strength sodium hydroxidesolution were added to a solution of 3.28 g (8.66 mmol) of methyl[5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]acetatein 70 ml of ethanol. The reaction mixture was stirred at roomtemperature for 5 hours. According to a TLC check (silica gel,dichloromethane/methanol 9:1), the reaction was complete. The reactionmixture was worked up by concentrating in a rotary evaporator andadjusting to pH 1-2 with 1N hydrochloric acid. The white suspension wasstored in a refrigerator for 4 hours, the precipitated solid wasfiltered off, and the resulting solid was dried in a vacuum drying ovenat 40° C. 3.12 g (8.55 mmol, yield 99% of theory) of the title compoundwere obtained.

ESI-MS: 365.15 [M+H]⁺

Separation of Enantiomers

2.518 g (8.55 mmol) of (+)-cinchonidine (rotation in CHCl₃: +218°) wereadded to a solution of 3.12 g (8.55 mmol) of[5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]aceticacid in 30 ml of methanol. The reaction mixture was stirred at 64° C.for 30 minutes and then slowly cooled. The precipitated solid wasfiltered off at ˜40° C., washed with warm methanol and diethyl ether andthen dried in a vacuum drying oven at 40° C. (288 mg). A furtherfraction of the crystallization was filtered off at room temperature,washed with warm methanol and diethyl ether and then dried in a vacuumdrying oven at 40° C. (1.24 g). The reaction solution was stored in arefrigerator for some hours and then the precipitated solid was washedwith warm methanol and diethyl ether and dried in a vacuum drying ovenat 40° C. (175 mg). After the mother liquor had been concentrated to 50ml, the precipitated solid was again filtered off, washed with warmmethanol and diethyl ether and then dried in a vacuum drying oven at 40°C. (355 mg).

The 4 fractions of the crystallization were each dissolved in a 1:1mixture of ethyl acetate and water and then adjusted to pH 1-0 withconcentrated HCl. After stirring for 15 minutes, the phases wereseparated. The aqueous phase was extracted with ethyl acetate. Thecombined organic phase was washed initially with water (1×) and thenwith saturated sodium chloride solution (1×), dried over magnesiumsulfate and filtered, and the solvent was removed in vacuo.

1st fraction of crystallization: 175 mg (rotation in CHCl₃: +70°)

2nd fraction of crystallization: 749 mg (rotation in CHCl₃: +65°)

3rd fraction of crystallization: 109 mg (rotation in CHCl₃: +74°)

4th fraction of crystallization: 208 mg (rotation in CHCl₃: +72°)

ESI-MS: 365.15 [M+H]⁺

56.45-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-{2-[4-(1-methylpiperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydroindol-2-one

200 mg (0.45 mmol) of BOP, 1.07 ml (6.17 mmol) of diisopropylethylamineand then 79 mg (0.43 mmol) of 1-(1-methylpiperidin-4-yl)piperazine wereadded to a solution of 150 mg (0.41 mmol) of[5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]aceticacid in 2 ml of dichloromethane. The reaction mixture was stirred atroom temperature overnight. 6 ml of a 2-molar NaOH were added to thereaction solution, and it was stirred at room temperature for 15minutes. The reaction mixture was diluted with ethyl acetate. The phaseswere separated and the aqueous phase was extracted with ethyl acetate(1×). The combined organic phase was again washed with water (1×) andsaturated sodium chloride solution (1×), dried over magnesium sulfateand filtered, and the solvent was evaporated in vacuo. The residue waspurified by chromatography on silica gel (Redisep cartridge, mobilephase gradient from 2 to 50% methanol in dichloromethane). 181 mg of thetitle compound were obtained as a white solid.

ESI-MS: 530.50 [M+H]⁺

56.5(+)-5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydroindol-2-one

16.3 mg (0.41 mmol, 60% w/w) of sodium hydride and, after 10 minutes, 96mg (0.41 mmol) of 2,4-dimethoxyphenylsulfonyl chloride were added to asolution, cooled to 0° C., of 180 mg (0.34 mmol) of5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydroindol-2-onein 2 ml of dimethylformamide. The reaction mixture was allowed to warmto room temperature and was stirred for a further 50 minutes. Theprogress of the reaction was followed by thin-layer chromatography(silica gel, dichloromethane/methanol 15:5). Water and ethyl acetatewere added to the reaction mixture. The two phases were then separatedand the aqueous phase was extracted once more with ethyl acetate (1×).The combined organic phase was washed with water (1×) and saturatedsodium chloride solution (1×), dried over magnesium sulfate andfiltered, and the solvent was evaporated in vacuo. The residue waspurified by preparative HPLC (RP, eluents acetonitrile/water, 0.01%TFA). 116 mg (0.16 mmol, 46%, 99% purity) of the title compound wereobtained as a white solid.

Rotation α (CHCl₃): plus rotation

ESI-MS: 730.55 [M+H]⁺

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 10.20 (bs, 1H); 8.10 (m, 1H); 7.95(m, 1H); 7.85 (d, 1H); 7.70 (d, 1H); 7.35 (d, 1H); 7.05 (t, 1H); 6.65(m, 2H); 4.10 (m, 2H); 3.95 (m, 2H); 3.85 (s, 3H); 3.65 (s, 3H); 3.60(m, 2H); 3.35 (m, 4H); 3.00 (m, 5H); 2.80 (s, 3H); 2.50 (s, 2H); 2.25(m, 2H); 1.85 (m, 2H); 1.00 (t, 3H).

III. Determination of the Biological Activity

1. Vasopressin V1b Receptor Binding Assay:

Substances:

The test substances were dissolved in a concentration of 10⁻² M in DMSOand further diluted to 5×10⁻⁴ M to 5×10⁻³ M. These serial DMSOpredilutions were diluted 1:10 with assay buffer. The substanceconcentration was further diluted 1:5 in the assay mixture (2% DMSO inthe mixture).

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1b receptor (clone3H2) were harvested and homogenized in 50 mM Tris-HCl and in thepresence of protease inhibitors (Roche complete Mini #1836170) using aPolytron homogenizer at intermediate setting for 2×10 seconds, andsubsequently centrifuged at 40 000×g for 1 h. The membrane pellet wasagain homogenized and centrifuged as described and subsequently taken upin 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen inliquid nitrogen at −190° C.

Binding Assay:

The binding assay was carried out by the method based on that of Taharaet al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (250 μl), membranes (50 μg/ml protein in incubationbuffer) from CHO-K1 cells with stably expressed human V1b receptors(cell line hV1b_(—)3H2_CHO) were incubated with 1.5 nM ³H-AVP(8-Arg-vasopressin, PerkinElmer #18479) in incubation buffer (50 mMTris, 10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionallywith increasing concentrations of test substance (displacementexperiment). The nonspecific binding was determined with 1 M AVP (Bachem#H1780). All determinations were carried out as triplicatedeterminations. After incubation (60 minutes at room temperature), thefree radioligand was filtered off by vacuum filtration (Skatron cellharvester 7000) through Wathman GF/B glass fiber filter mats, and thefilters were transferred into scintillation vials. The liquidscintillation measurement took place in a model 2000 or 2200CA Tricarbinstrument (Packard). Conversion of the measured cpm into dpm wascarried out with the aid of a standard quench series.

Analysis:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ³H-AVP for the recombinant human V1b receptors is 0.4nM and was used to determine the Ki.

2. Vasopressin V1a Receptor Binding Assay:

Substances:

The test substances were dissolved in a concentration of 10⁻² M in DMSO.Further dilution of these DMSO solutions took place in incubation buffer(50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4).

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1a receptor (clone5) were harvested and homogenized in 50 mM Tris-HCl and in the presenceof protease inhibitors (Roche complete Mini #1836170) using a Polytronhomogenizer at intermediate setting for 2×10 seconds, and subsequentlycentrifuged at 40 000×g for 1 h. The membrane pellet was againhomogenized and centrifuged as described and subsequently taken up in 50mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquidnitrogen at −190° C.

Binding Assay:

The binding assay was carried out by the method based on that of Taharaet al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (250 μl), membranes (20 μg/ml protein in incubationbuffer) from CHO-K1 cells with stably expressed human V1a receptors(cell line hV1a_(—)5_CHO) were incubated with 0.04 nM ¹²⁵I-AVP(8-Arg-vasopressin, NEX 128) in incubation buffer (50 mM Tris, 10 mMMgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionally with increasingconcentrations of test substance (displacement experiment). Thenonspecific binding was determined with 1 μM AVP (Bachem #H1780).Triplicate determinations were carried out.

After incubation (60 minutes at room temperature), the free radioligandwas filtered off by vacuum filtration (Skatron cell harvester 7000)through Wathman GF/B glass fiber filter mats, and the filters weretransferred into scintillation vials.

The liquid scintillation measurement took place in a model 2000 or2200CA Tricarb instrument (Packard). Conversion of the measured cpm intodpm was carried out with the aid of a standard quench series.

Analysis:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ¹²⁵I-AVP for the recombinant hV1a receptors wasdetermined in saturation experiments. A Kd of 1.33 nM was used todetermine the Ki.

3. Vasopressin V2 Receptor Binding Assay:

Substances:

The test substances were dissolved in a concentration of 10⁻² M in DMSO.Further dilution of these DMSO solutions took place in incubation buffer(50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4).

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V2 receptor (clone23) were harvested and homogenized in 50 mM Tris-HCl and in the presenceof protease inhibitors (Roche complete Mini #1836170) using a Polytronhomogenizer at intermediate setting for 2×10 seconds, and subsequentlycentrifuged at 40 000×g for 1 h. The membrane pellet was againhomogenized and centrifuged as described and subsequently taken up in 50mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquidnitrogen at −190° C.

Binding Assay:

The binding assay was carried out by the method based on that of Taharaet al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (250 μl), membranes (50 μg/ml protein in incubationbuffer) from CHO-K1 cells with stably expressed human V2 receptors (cellline hV2_(—)23_CHO) were incubated with 1-2 nM ³H-AVP(8-Arg-vasopressin, PerkinElmer #18479) in incubation buffer (50 mMTris, 10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionallywith increasing concentrations of test substance (displacementexperiment). The nonspecific binding was determined with 1 μM AVP(Bachem #H1780). Triplicate determinations were carried out.

After incubation (60 minutes at room temperature), the free radioligandwas filtered off by vacuum filtration (Skatron cell harvester 7000)through Wathman GF/B glass fiber filter mats, and the filters weretransferred into scintillation vials.

The liquid scintillation measurement took place in a model 2000 or2200CA Tricarb instrument (Packard). Conversion of the measured cpm intodpm was carried out with the aid of a standard quench series.

Analysis:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ³H-AVP for the recombinant hV2 receptors is 2.4 nMand was used to determine the Ki.

4. Oxytocin Receptor Binding Assay

Substances:

The substances were dissolved in a concentration of 10⁻² M in DMSO anddiluted with incubation buffer (50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH7.4).

Cell Preparation:

Confluent HEK-293 cells with transiently expressing recombinant humanoxytocin receptors were centrifuged at 750×g at room temperature for 5minutes. The residue was taken up in ice-cold lysis buffer (50 mMTris-HCl, 10% glycerol, pH 7.4 and Roche complete protease inhibitor)and subjected to an osmotic shock at 4° C. for 20 minutes. The lyzedcells were then centrifuged at 750×g at 4° C. for 20 minutes, theresidue was taken up in incubation buffer, and aliquots of 10⁷ cells/mlwere prepared. The aliquots were frozen at −80° C. until used.

Binding Assay:

On the day of the experiment, the cells were thawed, diluted withincubation buffer and homogenized using a Multipette Combitip(Eppendorf, Hamburg). The reaction mixture of 0.250 ml was composed of 2to 5×10⁴ recombinant cells, 3-4 nM ³H-oxytocin (PerkinElmer, NET 858) inthe presence of test substance (inhibition plot) or only incubationbuffer (total binding). The nonspecific binding was determined with 10⁻⁶M oxytocin (Bachem AG, H2510). Triplicate determinations were set up.Bound and free radioligand were separated by filtration under vacuumwith Whatman GF/B glass fiber filters with the aid of a Skatron cellharvester 7000. The bound radioactivity was determined by liquidscintillation measurement in a Tricarb Beta counter, model 2000 or2200CA (Packard).

Analysis:

The binding parameters were calculated by nonlinear regression analysis(SAS) in analogy to the LIGAND program of Munson and Rodbard (AnalyticalBiochem 1980; 107: 220-239). The Kd of ³H-oxytocin for the recombinanthOT receptors is 7.6 nM and was used to determine the Ki.

5. Determination of the Microsomal Half-Life:

The metabolic stability of the compounds of the invention was determinedin the following assay.

The test substances were incubated in a concentration of 0.5 μM asfollows: 0.5 μM test substance are preincubated together with livermicrosomes from different species (from rat, human or other species)(0.25 mg of microsomal protein/ml) in 0.05 M potassium phosphate bufferof pH 7.4 in microtiter plates at 37° C. for 5 min. The reaction isstarted by adding NADPH (1 mg/mL). After 0, 5, 10, 15, 20 and 30 min, 50μl aliquots are removed, and the reaction is immediately stopped andcooled with the same volume of acetonitrile. The samples are frozenuntil analyzed. The remaining concentration of undegraded test substanceis determined by MSMS. The half-life (T½) is determined from thegradient of the signal of test substance/unit time plot, it beingpossible to calculate the half-life of the test substance, assumingfirst order kinetics, from the decrease in the concentration of thecompound with time. The microsomal clearance (mCl) is calculated frommCl=In2/T½/(content of microsomal protein in mg/ml)×1000 [ml/min/mg](modified from references: Di, The Society for Biomoleculur Screening,2003, 453-462; Obach, D M D, 1999 vol 27. N 11, 1350-1359).

6. Methods for In Vitro Determination of the Cytochrome P450 (CYP)Inhibition

Luminescent Substrates for 2C9 and 3A4:

0.4 mg/ml human liver microsomes are preincubated with the testsubstances to be investigated (0-20 μM), the CYP-specific substrates, in0.05 M potassium phosphate buffer of pH 7.4 at 37° C. for 10 min. TheCyp-specific substrate for CYP 2C9 is luciferin H, and for CYP 3A4 isluciferin BE. The reaction is started by adding NADPH. After incubationat RT for 30 min, the luciferin detection reagent is added, and theresulting luminescence signal is measured (modified from reference:Promega, Technical Bulletin P450-GLO™ Assays).

Midazolam CYP 3A4 Time-Dependent Inhibition

The assay consists of 2 parts. Firstly, the test substance ispreincubated with the liver microsomes (with NADPH=preincubation, thenaddition of the substrate; in the second part the substrate and the testsubstance are added simultaneously=coincubation.

Preincubation:

0.05 mg/ml microsomal protein (human liver microsomes) are preincubatedwith 0-10 μM (or 50 μM) test substance in 50 mM potassium phosphatebuffer for 5 min. The reaction is started with NADPH. After 30 min 4 μMmidazolam (final concentration) are added, and incubation is continuedfor 10 min. 75 μl of the reaction solution are removed after 10 min, andstopped with 150 μl of acetonitrile solution.

Coincubation:

0.05 mg/ml microsomal protein (human liver microsomes) are preincubatedwith 4 μM midazolam (final concentration) and 0-10 μM (or 50 μM) testsubstance in 50 mM potassium phosphate buffer for 5 min. The reaction isstarted with NADPH. 75 μl of the reaction solution are removed after 10min and stopped with 150 μl of acetonitrile solution. The samples arefrozen until the MSMS analysis (modified from references: Obdach,Journal of Pharmacology & Experimental Therapeutics, Vol 316, 1,336-348, 2006; Walsky, Drug Metabolism and Disposition Vol 32, 6,647-660, 2004).

7. Method for Determining the Solubility in Water (in mg/ml)

The solubility in water of the compounds of the invention can bedetermined for example by the so-called shake flask method (as specifiedin ASTM International: E 1148-02, Standard test methods for measurementof aqueous solubility, Book of Standards Volume 11.05.). This entails anexcess of the solid compound being put into a buffer solution with aparticular pH (for example phosphate buffer of pH 7.4), and theresulting mixture being shaken or stirred until equilibrium has been setup (typically 24 or 48 hours, sometimes even up to 7 days). Theundissolved solid is then removed by filtration or centrifugation, andthe concentration of the dissolved compound is determined by UVspectroscopy or high pressure liquid chromatography (HPLC) by means ofan appropriate calibration plot.

8. Results

The results of the receptor binding investigations are expressed asreceptor binding constants [K_(i)(V1b)] or selectivities[K_(i)(V1a)/K_(i)(V1b)]. The results of the investigation of themetabolic stability are indicated as microsomal clearance (mCl).

The compounds of the invention show very high affinities for the V1breceptor in these assays (maximally 100 nM, or maximally 10 nM,frequently <1 nM). The compounds also show high selectivities vis-à-visthe V1a and the oxytocin (OT) receptor and a good metabolic stability,measured as microsomal clearance.

The results are listed in table 2. The numbers of the compounds refer tothe synthesis examples.

TABLE 2 Ex- K_(i)(h − V1b)* K_(i)(h − V1a)/ K_(i)(h − OT)/ ample [nM]K_(i)(h − V1b)* K_(i)(h − V1b)* 1 +++ +++ +++ 2 +++ +++ +++ 3 +++ ++ +++4 +++ ++ +++ 5 ++ +++ +++ 6 ++ +++ +++ 7 ++ + +++ 8 ++ ++ +++ 10 ++ ++ +11 +++ +++ +++ 12 ++ +++ +++ 13 ++ ++ +++ 14 ++ + +++ 15 ++ + +++ 16+++ + +++ 17 ++ + +++ 18 ++ + +++ 19 +++ ++ ++ 20 ++ + ++ 21 +++ ++ +++22 ++ + +++ 23 +++ + +++ 26 +++ + +++ 31 + +++ + 33 ++ +++ +++ 35 ++ + +38 +++ +++ +++ 39 +++ ++ +++ 40 ++ + +++ 41 +++ + + 42 +++ + + 43 +++ +++++ 45 ++ + +++ 46 ++ ++ + 50 + + ++ 51 ++ +++ ++ 52 ++ ++ + 53 ++ ++ ++*h = human Key: K_(i)(V1b) K_(i)(h − V1a)/K_(i)(h − V1b) K_(i)(h −OT)/K_(i)(h − V1b) + >10-100 nm 10-<25 10-<25 ++ 1-10 nm 25-75 25-75 +++<1 nm >75 >75

The invention claimed is:
 1. A compound of the formula I.A

in which R¹ and R² are independently of one another hydrogen,C₁-C₃-alkyl, C₁-C₃-fluoroalkyl, C₁-C₃-alkoxy, C₁-C₃-fluoroalkoxy,halogen or CN; R³ is hydrogen or C₁-C₄-alkyl; R⁴ is ethoxy, fluorinatedethoxy or isopropoxy; R⁵ is hydrogen or methyl; R⁶ is Br, Cl, F or CN;R⁷ is Cl, F or CN; X¹ is O, NH or CH₂; X² and X³ are N or CH, with theproviso that X² and X³ are not simultaneously N; and X⁴ is N or CH; andtheir pharmaceutically acceptable salts and prodrugs thereof.
 2. Acompound of claim 1, in which R¹ is hydrogen, methoxy, ethoxy,fluoromethoxy, difluoromethoxy or trifluoromethoxy.
 3. A compound ofclaim 1, in which R² is hydrogen or methoxy.
 4. A compound of claim 1,in which R¹ and R² are methoxy.
 5. A compound of claim 1, in which R³ ishydrogen, methyl or ethyl.
 6. A compound of claim 1, in which R⁴ isethoxy and R⁵ is H.
 7. A compound of claim 1, in which R⁴ is2,2-difluoroethoxy or 2,2,2-trifluoroethoxy and R⁵ is H.
 8. A compoundof claim 1, in which R⁶ and R⁷ are not simultaneously CN.
 9. A compoundof claim 1, in which at least one of the radicals R⁶ and R⁷ is F.
 10. Acompound of claim 9, in which R⁷ is F and R⁶ is F, Cl, Br or CN.
 11. Acompound of claim 1, in which X² is N and X³ is CH.
 12. A compound ofclaim 1, in which X² is CH and X³ is N.
 13. A compound of claim 1, inwhich X² is CH and X³ is CH.
 14. A compound of claim 1, in which X¹ isO.
 15. A compound of claim 1, in which X¹ is NH.
 16. A compound of claim1, in which X⁴ is N.
 17. A compound of claim 1 in which R¹ is methoxy;R² is methoxy; R³ is methyl or ethyl; R⁴ is ethoxy; R⁵ is H; R⁶ is Cl orCN; R⁷ is F; X¹ is NH; X² is N; X³ is CH; and X⁴ is N.
 18. A compound ofclaim 1 in which R¹ is methoxy; R² is methoxy; R³ is methyl or ethyl; R⁴is ethoxy; R⁵ is H; R⁶ is Cl or CN; R⁷ is F; X¹ is NH; X² is CH; X³ isN; and X⁴ is N.
 19. A compound of claim 1 in which R¹ is methoxy; R² ismethoxy; R³ is methyl or ethyl; R⁴ is ethoxy; R⁵ is H; R⁶ is Cl or CN;R⁷ is F; X¹ is CH₂; X² is N; X³ is CH; and X⁴ is N.
 20. A compound ofclaim 1 in which R¹ is methoxy; R² is methoxy; R³ is methyl or ethyl; R⁴is ethoxy; R⁵ is H; R⁶ is Cl or CN; R⁷ is F; X¹ is CH₂; X² is CH; X³ isN; and X⁴ is N.
 21. A compound of claim 1 in which R¹ is methoxy or H;R² is methoxy; R³ is methyl or ethyl; R⁴ is ethoxy; R⁵ is H; R⁶ is Cl orCN; R⁷ is F; X¹ is O; X² is N; X³ is CH; and X⁴ is N.
 22. A compound ofclaim 1 in which R¹ is methoxy or H; R² is methoxy; R³ is methyl orethyl; R⁴ is ethoxy; R⁵ is H; R⁶ is Cl or CN; R⁷ is F; X¹ is O; X² isCH; X³ is N; and X⁴ is N.
 23. A compound of claim 1 in which R¹ ismethoxy; R² is methoxy; R³ is methyl or ethyl; R⁴ is ethoxy; R⁵ is H; R⁶is Cl or CN; R⁷ is F; X¹ is NH; X² is N; X³ is CH; and X⁴ is CH.
 24. Acompound according to claim 1, or a pharmaceutically acceptable saltthereof, selected from the group consisting of:4-(1-Methylpiperidin-4-yl)piperazin-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(+)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;(−)-4-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Methylpiperazin-1-yl)piperidine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Methylpiperazin-1-yl)piperidine-1-[5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Methylpiperidin-4-yl)piperazine-1-[5-cyano-3-(2-ethoxyphenyl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-cyano-3-(2-ethoxyphenyl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Ethylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-5-cyano-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Methylpiperazin-1-yl)piperidine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Methylpiperazin-1-yl)piperidine-1-[5-cyano-3-(2-ethoxyphenyl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Ethylpiperazin-1-yl)piperidine-1-[5-cyano-3-(2-ethoxyphenyl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Ethylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-5-cyano-3-(2-ethoxyphenyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Methylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Ethylpiperidin-4-yl)piperazine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Ethylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Methylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Ethylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;1′-Methyl[4,4]bipiperidinyl-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-pyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;1′-Ethyl[4,4]bipiperidinyl-1-[5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-pyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Methylpiperazin-1-yl)piperidine-1-[5-chloro-3-[2-(2,2-difluoroethoxy)phenyl]-1-(2,4-dimethoxyphenylsulfonyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Methylpiperidin-4-yl)piperazine-1-[5-chloro-3-[2-(2,2-difluoroethoxy)phenyl]-1-(2,4-dimethoxyphenylsulfonyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;1′-Methyl[4,4]bipiperidinyl-1-[5-chloro-3-[2-(2,2-difluoroethoxy)phenyl]-1-(2,4-dimethoxyphenylsulfonyl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Methylpiperidin-4-yl)piperazine-1-[1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-pyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Methylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Ethylpiperidin-4-yl)piperazine-1-[1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-pyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(1-Ethylpiperidin-4-yl)piperazine-1-[1-phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Methylpiperazin-1-yl)piperidine-1-[1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-pyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Methylpiperazin-1-yl)piperidine-1-[1-phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;4-(4-Ethylpiperazin-1-yl)piperidine-1-[1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxy-pyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]carboxamide;5-Cyano-1-(2,4-dimethoxybenzenesulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;5-Cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;1-Phenylsulfonyl-5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;5-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;5-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;5-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-1-(4-methoxy-2-trifluoromethoxyphenyl-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;1-Phenylsulfonyl-5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;6-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;6-Chloro-3-(2-ethoxypyridin-3-yl)-5-fluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;6-Chloro-3-(2-ethoxypyridin-3-yl)-5-fluoro-1-(4-methoxy-2-trifluoromethoxyphenyl-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;1-Phenylsulfonyl-6-chloro-3-(2-ethoxypyridin-3-yl)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;6-Chloro-3-(2-ethoxypyridin-3-yl)-5-fluoro-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;3-(2-Ethoxypyridin-3-yl)-5,6-difluoro-1-(4-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;3-(2-Ethoxypyridin-3-yl)-5,6-difluoro-1-(2-methoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl-4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;3-(2-Ethoxypyridin-3-yl)-5,6-difluoro-1-(4-methoxy-2-trifluoromethoxyphenylsulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate;1-Phenylsulfonyl-3-(2-ethoxypyridin-3-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate; and(+)-5-Chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydroindol-2-one.25. A pharmaceutical composition comprising at least one compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof, andat least one pharmaceutically acceptable carrier.